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Review

Epigenetic Regulation of Chondrocytes and Subchondral Bone in Osteoarthritis

by
Hope C. Ball
1,2,3,*,
Andrew L. Alejo
1,2,
Trinity K. Samson
1,2,4,
Amanda M. Alejo
1,2 and
Fayez F. Safadi
1,2,3,5,*
1
Department of Anatomy and Neurobiology, Northeast Ohio Medical University, Rootstown, OH 44272, USA
2
Musculoskeletal Research Group, Northeast Ohio Medical University, Rootstown, OH 44272, USA
3
GPN Therapeutics, Inc., REDI Zone, Rootstown, OH 44272, USA
4
Department of Orthopaedic Surgery, Akron Children’s Hospital, Akron, OH 44308, USA
5
Rebecca D. Considine Research Institute, Akron Children’s Hospital, Akron, OH 44302, USA
*
Authors to whom correspondence should be addressed.
Life 2022, 12(4), 582; https://doi.org/10.3390/life12040582
Submission received: 28 February 2022 / Revised: 30 March 2022 / Accepted: 4 April 2022 / Published: 14 April 2022
(This article belongs to the Special Issue Gene/Stem Cell/Molecular Therapy of Craniofacial and Bone Diseases)
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Abstract

:
The aim of this review is to provide an updated review of the epigenetic factors involved in the onset and development of osteoarthritis (OA). OA is a prevalent degenerative joint disease characterized by chronic inflammation, ectopic bone formation within the joint, and physical and proteolytic cartilage degradation which result in chronic pain and loss of mobility. At present, no disease-modifying therapeutics exist for the prevention or treatment of the disease. Research has identified several OA risk factors including mechanical stressors, physical activity, obesity, traumatic joint injury, genetic predisposition, and age. Recently, there has been increased interest in identifying epigenetic factors involved in the pathogenesis of OA. In this review, we detail several of these epigenetic modifications with known functions in the onset and progression of the disease. We also review current therapeutics targeting aberrant epigenetic regulation as potential options for preventive or therapeutic treatment.

1. Introduction

Epigenetics, as a word, has been present in the biological vocabulary since it was coined by C.H. Waddington in the 1930s [1]. Since then, the concepts this word describes have undergone extensive changes, from a broad overall postulation on the workings of molecular development to the more modern term used to refer to a multitude of genetic and transcriptomic chromatic regulators [1,2]. The scope and breadth of these regulators can vary depending on context but commonly incorporate nucleotide or amino acid modifications such as methylation/demethylation, acetylation/deacetylation, phosphorylation, glycosylation, ubiquitination, transposable elements, non-coding RNAs (ncRNAs), small-interfering RNAs (siRNAs), and microRNAs (miRNAs). More recently, scientists have been expanding studies of these sporadic or temporal cellular events to determine the influence of environmental changes during development (environmental epigenetics) and/or inherited (transgenerational epigenetics) on epigenetic regulators [3,4]. Furthermore, studies are beginning to shed light on how epigenetic changes affect normal physiological functions.
Epigenetic modifications during aging have been shown to negatively affect tissue physiological function by themselves or in conjunction with various environmental factors, such as weight, stress, or drug/alcohol usage [5,6]. Recent studies have linked changes in epigenetic regulation to the development and/or progression of a wide range of human diseases. DNA demethylation, aberrant histone methylation, and histone enzymatic activity have been linked to cancer and tumor metastases [7,8,9]. Similarly, epigenetic dysregulation has been linked to cardiovascular disease [5,10], and diabetic kidney disease [11,12].
The development and progression of osteoarthritis (OA) are also negatively affected by epigenetic dysregulation. OA is a debilitating joint disease and instigator of chronic disability that affects approximately half of the global population over the age of 65, incurring a substantial socioeconomic burden (USD 128 billion in 2003 alone and rising) [13,14,15,16]. The prevalence of this disease is expected to continue to grow as global life expectancies rise [17]. OA pathophysiology is most associated with synovitis (chronic synovial inflammation), ectopic new bone formation (osteophytes), abnormal subchondral bone remodeling, and the degradation of articular cartilage due to physical and proteolytic degradation [18,19,20] (Figure 1). However, OA is a multifactorial disease that also affects the meniscus, ligament structures, and infrapatellar fat pad, meaning that it is a whole joint disease [21,22]. Known risk factors for the disease include microenvironment and mechanical stressors, physical activity levels, health status, obesity, genetic predisposition, and age [23,24,25]. One of the biggest difficulties in the understanding and treatment of the disease is that OA is symptomatic only in approximately 30% of patients in later disease stages, making the detection of early biomarkers difficult [26,27]. At present, no disease-modifying drugs are available to decelerate or reverse OA. Current OA treatments are limited to pharmacological pain management and arthroplasty, an irreversible surgical procedure that typically requires revisional surgery in 10–15 years [28,29].
One of the biggest problems in the treatment of OA is that the affected tissue, articular cartilage, is unable to regenerate to repair mechanical or enzymatic damage. Articular chondrocytes, the resident cell type present in cartilage, synthesize an extracellular matrix (ECM) capable of withstanding biomechanical pressures and responsible for smooth joint articulation. Under normal conditions, chondrocytes are quiescent and catabolic and anabolic factors are balanced to maintain joint homeostasis. When damage occurs, chondrocytes cannot regenerate the damaged tissue and actively participate in cartilage destruction by enhancing the production of catabolic proteases [21,30]. The molecular basis for this switch in chondrocyte function remains poorly understood, but aberrant gene expression and epigenetic modifications are implicated [31].
OA is known to have genetic components associated with disease onset and progression with dozens of loci associated with the disease [32]. These loci alter gene expression and contribute to OA by either altering gene expression patterns or through post-translational modifications [33]. Chondrocyte gene expression is regulated by a variety of epigenetic mechanisms including the methylation of DNA and histones, histone acetylation, ncRNAs and polycomb group proteins (PRCs) [34]. In this review, we will discuss these epigenetic mechanisms and how they contribute to the onset and progression of OA.

2. Methods

A PUBMED literature review was conducted searching for original papers on epigenetic regulation in OA. The key words used included “DNA methylation in osteoarthritis”, “epigenetics and osteoarthritis”, “epigenetics and synovium in osteoarthritis”, “histone modification and osteoarthritis”, “polycomb and osteoarthritis”, “miRNA and osteoarthritis”, “siRNA and osteoarthritis”, “non-coding RNA and osteoarthritis”, “epigenetic regulation of subchondral bone”, “osteoarthritis therapeutics”, and “epigenetic therapies and osteoarthritis”.

3. DNA Methylation

DNA methylation involves the addition of a methyl group to a specific location along the DNA strand. This reaction is catalyzed by DNA methyltransferases (DNMTs) and there are currently four known mammalian enzymes: DNMT1, DNMT3a, DNMT3b and DNMT3L [35,36]. The biological importance of this addition is that it alters the three-dimensional conformation of the DNA and, depending on the location, can either enhance or inhibit the ability of transcription factors and/or associated proteins to bind DNA [37,38]. In OA, changes in DNA methylation patterns are some of the most widely studied epigenetic phenomenon.
Early studies of DNA methylation patterns associated with OA were targeted primarily on candidate genes already known to be associated with OA pathophysiology. Candidates often included catabolic cytokines and chemokines such as the matrix metalloproteinases (MMP-3, MMP-9, and MMP-13) and aggrecanases A disintegrin and metalloproteinase with thrombospondin motifs 4 and 5 (ADAMTS-4 and ADAMTS-5) that are upregulated in OA and contribute to proteolytic cartilage degradation [39,40]. Proinflammatory molecules, such as interleukins (IL-1β, IL-6 and IL-8), inducible nitric oxide synthase (iNOS) and tumor necrosis factor-alpha (TNF-α), responsible for the initiation and maintenance of chronic joint inflammation were also targeted [41,42]. The results from these studies determined that the promoters of these catabolic factors are demethylated in OA, permitting increased catabolic gene expression [34,43,44,45]. Anabolic factors known to be downregulated in OA pathogenesis, such as cartilage ECM genes type-II collagen (Col2α1) and aggrecan (ACAN) were targeted as well and found to be hypermethylated, inhibiting their expression [46,47]. Studies into DNA methylation changes during OA have also focused on signaling pathways known to be altered in articular cartilage and subchondral bone during OA. For instance, the Wnt pathway is known to be upregulated during OA progression and epigenetic changes have been detected that altered sclerostin (SOST) and Wnt-ligand secretion mediator (WLS) function to increase inflammation and endochondral ossification, respectively [41,48].
More recently, OA DNA methylation studies have switched to non-targeted genome-wide methylome studies to identify novel genes or regions affected by the disease. The standardization techniques used in these non-targeted genome-wide assays make comparisons between datasets easier to manage and promote more collaborative studies, which increase sample sizes and allow for examinations of OA-specific DNA methylation changes at various stages of disease progression and analyses of global datasets. Analyses of these global datasets are beginning to detect regional and/or ethnic methylations that contribute to disease susceptibility. For instance, meta-analyses of single-nucleotide polymorphisms (SNPs) of European, Japanese and East Asian populations have identified region-specific SNPs in type-11α1 collagen (COL11α1), vascular endothelial growth factor (VEGF) and growth differentiation factor 5 (GDF5) that enhance susceptibility to OA [40,49,50,51,52,53,54]. Furthermore, these large-scale analyses can detect sex-specific and location-specific differences in susceptibility loci to better predict predilection to hip versus knee OA within a population [40,55,56,57]. Future studies identifying OA-specific SNPs and loci differences within populations will continue to improve our knowledge of OA-affected genetic differences and will increase risk prediction.

4. Histone Methylation

Genetic architecture plays and enormous role in transcriptional control. The structure and accessibility of DNA for transcriptional activity are partly governed by the location and function of histones, conserved regions of DNA enriched with positively charged amino acids such as lysine (K) and arginine (R) [41,58]. These positively charged regions interact tightly with the negatively charged DNA backbone and accessory DNA binding proteins to form tightly wound regions called nucleosomes [58,59]. This winding makes the DNA inaccessible, which protects it from damage and regulates the transcriptional control of the affected regions [58,60]. An additional level of control governing histone-DNA interactions are post-transcriptional modifications to the side chains of the amino acids comprising the histone. The various modifications known to occur include sumoylation (the covalent attachment of small ubiquitin-like modifiers (SUMO) to lysine residues), phosphorylation, ubiquitination (the covalent attachment of ubiquitin to lysine residues), and poly (ADP)-ribosylation [61,62,63,64,65]. The two most widely known and widely studied post-transcriptional modifications in the pathogenesis of OA, however, are histone methylation and histone acetylation (Figure 2). The process of histone methylation and its relevance to the pathophysiology of OA will be discussed here and histone acetylation in the following subsection.
Histones are methylated by histone methyltransferases (HMTs) that catalyze the addition of a methyl group to specific arginine or lysine residues on histone tail side chains [41,65]. This reaction is reversible and the added methyl groups can be removed through the actions of histone demethyltransferases (HDMTs). Unlike DNA methylation, the effects of histone methylation depend highly on the site of methylation as well as the degree of methylation (mono-, di- or trimethylation) [65,66]. Some of the most well-studied sites for histone methylation occur on lysine residues associated with histone 3 (H3) [65,67,68]. For example, the inhibition of HMT activity at H3 lysine 4 (H3K4) reduced inflammation by preventing iNOS and cyclooxygenase-2 (COX-2) expression in chondrocytes, and methylation at lysines 9, 20 and 24 (H3K9, H3K20 and H3K24) are known to be altered in OA [38,69,70,71,72]. Histone methylation changes are also known to affect the expression of SOX-9 (SRY-box transcription factor-9), an important transcription factor regulating COL2α1 expression. SOX-9 expression is downregulated in OA and studies of epigenetic modifiers have linked SOX-9 inhibition to the increased methylation of H3K27 [46,73,74,75]. Furthermore, the methylation of the NFATC1 (Nuclear Factor of Activated T-cells-1) promoter has been shown to be increased in OA and contributes to chondrocyte dysfunction [76,77].
Perhaps one of the best examples of the role of HMTs in OA pathology is that of DOT1-like histone lysine methyltransferase (DOT1L). DOT1L was one of the first methyltransferases identified as associated with OA and subsequent studies have shed additional light on the protective role of this enzyme in cartilage and chondrocyte biology [78]. DOT1L is the only known mammalian HMT to catalyze the methylation of H3 lysine79 (H3K79) [79]. The protective mechanism of DOT1L is two-fold: it inhibits sirtuin 1 (SIRT1), a highly conserved deacetylase that contributes to OA progression, and also methylates promoters of lymphoid enhancer-binding factor 1 (LEF1) and T-cell factor 1 (TCF1) to modulate wingless-type (Wnt) signaling in chondrocytes [80,81]. In patients suffering from OA, H3K79 methylation was reduced, resulting in Wnt pathway activation and increased cartilage degradation in humans as well as in murine OA models [82,83].
KDM6B (JMJD3) is emerging as a demethylase of interest in the onset and progression of OA. KDM6B catalyzes the removal of methyl groups from histone 3 lysine 27 (H3K27) and functions to modulate cartilage anabolism and homeostasis [69,84]. In chondrocytes, the knockdown of KDM6B in mice results in abnormal bone and cartilage development and accelerates the progression of OA [84,85]. Furthermore, KDM6B is associated with chondrocyte hypertrophy by increasing Runt-related transcription factor 2 (RUNX2) and Indian hedgehog (IHH) signaling [85,86]. The overactivation of RUNX2 also negatively impacts OA pathogenesis by enhancing subchondral bone ossification and remodeling [84,85].

5. Histone Acetylation

Similar to histone methylation, dysregulated histone acetylation/deacetylation is known to play a role in enhanced proinflammatory cytokine and chemokine activity in both rheumatoid and osteoarthritis [87,88]. The addition or removal of an acetyl group from histones affects gene transcription and accessibility (Figure 2). Histone acetyltransferases (HATs) catalyze the addition of an acetyl group to a histone or histone sidechain, which loosens DNA-histone binding and enhances gene transcription [89]. Conversely, the removal of acetyl groups is catalyzed by histone deacetylases (HDACs) that are recruited by transcription factors and protein complexes to enhance the binding between histones and DNA to silence transcription [87,90]. Additionally, both HATs and HDACs by themselves are known to interact with and destabilize non-histone-associated proteins and co-factors, leading to cellular dysfunction [91,92]. Unfortunately, this interaction with additional accessory proteins and/or transcription factors outside of DNA–histone interactions places limitations on the use of HAT and HDAC knockout animal models [18,93].
Of these reactions, much more is known about HDACs and their role in the development and progression of OA. HDACs comprise four separate classes divided by enzymatic structure, substrate usage, function, and location. Class I (1, 2, 3 and 8) and Class II (4, 5, 6, 7, 9 and 10) HDACs use zinc as a common substrate, while Class III HDACs, also referred to as sirtuins (Sirt 1-7), utilize nicotinamide adenine dinucleotides (NAD+) [87,94,95]. Class I enzymes are vital for cell survival and regulate gene transcription and DNA replication during development [96,97]. Knockout models of these are embryonically lethal. Class II enzymes have weaker enzymatic activity but are more tissue specific in their function [98,99]. Class III enzymes (the Sirts) possess the highest enzymatic activity of the HDACs and studies have shown that their activity affects a multitude of different pathways including (but not limited to) aging, inflammation, bone formation, maintenance, and metabolism [100,101].
Several studies have examined the role of HDACs in osteoarthritis. During OA development and progression, the activity of matrix catabolic factors is elevated, while anabolic factors are suppressed. Recently, studies on diseased cartilage have linked HDAC activity to reductions in anabolic factors. For instance, OA chondrocytes were found to have elevated levels of HDACs 1 and 2 which can inhibit the expression of key anabolic factors Col2α1 and ACAN [89,102,103]. In vitro studies have shown that Runx2, known to stimulate chondrocyte hypertrophy and MMP-13 production, is inhibited by HDAC4 but this interaction requires better study in vivo prior to therapeutic assessment [104,105,106]. HDAC7 is elevated in diseased OA cartilage and studies of the mechanism in murine models have linked it to elevated MMP-13 expression [107].
The expression of some HDACs, however, is known to have chondroprotective properties. SIRT6, for instance, plays a protective role in human and murine chondrocytes. In studies of human OA, SIRT6 expression is decreased in articular cartilage, and the overexpression of Sirt6 in mice reduces cartilage damage and the expression of proinflammatory cytokines and chemokines [108]. SIRT1, linked to increased Col2α1 expression, is also related to protective functions and SIRT1 expression is known to decline during OA in human chondrocytes and in subchondral osteoblasts [109,110]. Finally, the continuing development of knockout mouse models of HDACs 3-5 and HDAC7 allows for the continuation of more focused studies of endochondral bone formation and the changes that occur with age-related or induced post-traumatic osteoarthritis [111,112].
HDAC activity in OA is not limited to chondrocytes and cartilage. Synovial tissues are known to contribute to chronic joint inflammation through the secretion of proinflammatory cytokines and chemokines such as IL-6, IL-1β and TNF-α [113]. The best known function of IL-6 in OA is proinflammatory, but IL-6 also stimulates MMP-13 expression and activates osteoclast activity in subchondral bone, enhancing skeletal remodeling [114]. Epigenetic studies into IL-6 expression in the synovium of OA demonstrated that the promoter region of IL-6 is hypo-methylated, and the promoter histone region is hyper-acetylated, leading to increased IL-6 production [115]. While there are fewer studies on the epigenetic regulation of synovial tissues in OA, these findings demonstrate that the modulation of synovial epigenetics may be of interest for future studies towards pharmacological interventions.

6. Polycomb Repressive Complexes (PRCs)

Polycomb repressive complexes (PRCs) are key enzymes for regulating and modifying chromatin structure and histones. Polycomb repressive complex 1 (PRC1) and Polycomb repressive complex 2 (PRC2) are the two main repressive PcG protein complexes that contribute to chromatin compaction and play a crucial role during development, cell proliferation, and differentiation (Figure 3) [116,117]. PRCs are important in the silencing of genes globally, particularly during mitotic cycles that can act as regulatory mechanisms. Additionally, PRC proteins are biologically essential throughout development from embryogenesis to adulthood, particularly in the regulation of imprinted genes [118,119,120].
PRC1, composed of the subunits BMI1, PHC, CBX, and RING1A/B, is involved in transcriptional repression through the ubiquitination of histone 2 lysine 119 (H2K119) [121,122,123]. PRC2 is a chromatin-modifying enzyme that catalyzes the trimethylation of histone H3 at lysine 27 (H3K27), which regulates gene expression [124]. PRC2 contains four core subunits, SUZ12, EED, EZH1/EZH2, and RBBP4/7, which form two functional lobes [125,126]. The catalytic lobe that methylates H3K27 is comprised of the methyltransferase subunits enhancer of Zeste 1 polycomb repressive complex subunit-1 (EZH1) or enhancer of Zeste 2 polycomb repressive complex subunit-2 (EZH2), a binding protein called embryonic ectoderm development (EED), and the scaffold protein Zeste 12 homolog (SUZ12) [127,128]. The targeting lobe consists of SUZ12 and RBBP4/7 [125,129].
Studies into the epigenetic regulation of PRCs in the pathogenesis of human OA have recently paid particular attention to the importance of EZH2 in the development and progression of the disease. EZH2 has been found to be upregulated in both cartilage and chondrocytes of human OA patients [130,131] and in the cartilage of mice following the induction of post-traumatic OA via the destabilization of the medial meniscus (DMM) surgery [130,132,133]. This upregulation of EZH2 results in the enhanced expression of proinflammatory cytokines/chemokines (IL-1β, nitric oxide (NO) and IL-6), increased ECM catabolism via increased activity of MMPs and mediates Wnt pathway inhibitor-secreted frizzle-related protein (SFRP-1) [131,134]. While these findings seem to suggest that the EZH2 inhibition in cartilage would be undoubtedly beneficial, other studies have pointed out that the timing of ablation is important to the maintenance of chondrocyte homeostasis. A tissue-specific mouse EZH2 knockout mouse model showed enhanced cartilage destruction following the induction of post-traumatic OA via medial meniscectomy (MMx) surgery, suggesting that EZH2 plays a selective chondroprotective role [135]. A conditional knockout (cKO) of EZH2 in mouse mesenchymal stem cells resulted in a smaller body size and shorter limbs [136]. A histological analysis of the proximal tibias of one day and three-week-old EZH2 cKO pups revealed an abnormality in growth plate development, which was represented in the reduced distance between the surface of articular cartilage and the hypertrophic zone [136]. A reduction in distance between epiphysis and the hypertrophic zone is associated with a shorter proliferative area in the one-day-old EZH2 cKO pups and a reduced hypertrophic zone in the three-week-old EZH2 cKO mice. The importance of EZH2 function in chondrocytes and growth plate development is indicated by the reduced chondrocytes proliferation and accelerated hypertrophy in EZH2 cKO mice [136]. More studies are needed to assess the true role of EZH2 in OA pathophysiology.
PRC2 maintains gene transcription through alterations in cellular genetic makeup that govern normal cellular development. PRC2 is modulated by accessory subunits as well as various modifications to either stimulate or inhibit its activity on H3K27. Histone modifications and dense chromatin stimulate PRC2, while active chromatin inhibits it to prevent the spreading of H3K27 methylation [137,138]. PRC2 is necessary for normal skeletal and cartilage growth. When certain subunits of PRC2 are deficient, cartilaginous abnormalities can occur. For example, when EED is deficient, there have been reports that there is aberrant signaling activation in the Wnt pathway which causes premature differentiation, ultimately leading to kyphosis and accelerated chondrocyte hypertrophic differentiation [139]. In addition, the overactivation of TGF-β led to a reduction in chondrocyte proliferation with growth defects [140]. The functional activity of Z hypoxia-inducible transcription factor 1α (Hif1α) is required to maintain chondrocyte viability within the central region of the growth plate, and EED deficiency decreases Hif1α, ultimately leading to hypoxic cell death [139].

7. Non-Coding RNAs (ncRNAs)

Only approximately 1.2% of the human genome consists of coding regions, indicating the profound role and potential utility of non-coding regions [141]. Non-coding RNA (ncRNA) is a term applied to RNAs that do not code for proteins and that are sometimes thought of as “junk RNA” [142]. However, some ncRNAs have been known to have biological functions for decades, with early studies identifying roles in the regulation of chromosomes compaction (Xist), and in cell-type specific nuclear organization [143,144,145]. Further studies have supported the role of ncRNAs in epigenetic regulation and the remodeling of chromatin, although these roles are still being debated [146,147]. The term ncRNA includes a wide range of molecules such as small interfering RNAs (siRNAs) microRNAs (miRNAs), small nucleolar RNAs (snoRNAs), small nuclear RNAs (snRNAs), long non-coding RNAs (lncRNAs), and, more recently, circular RNAs (circRNAs), all of which have been implicated in the pathogenesis of OA [148,149,150].
siRNAs are double stranded, non-coding RNAs approximately 21–23 nucleotides in length (Figure 4) that typically have one specific target [151]. siRNAs are known to protect the genome from exogenous or invasive nucleic acids, such as viruses and transposons [152]. siRNAs can induce target degradation after translation through the formation of an RNA-induced silencing complex (RISC) or directly target mRNAs for degradation through base pair complementarity (RNAi) [152,153]. The role of siRNAs in the onset and development of OA is ever expanding. Given that OA is a polygenic disease, researchers typically focus the siRNA discovery of chondrocytes, cartilage, and synovium on one aspect, such as chronic inflammation or matrix degradation. For instance, the siRNA-mediated knockdown of ADAMTS-5 and MMP-13 through intra-articular injection ameliorated cartilage damage and inflammation following DMM in mice [154,155]. Similar findings were reported when siRNA targeting MMP-13 were delivered using intra-articular nanoparticle delivery methods [156]. RNA-silencing was also found to be effective at inhibiting inflammation through the targeting of TNFα and Transforming growth factorβ-activated kinase-1 (TAK1) in a collagen-induced murine models [157]. These findings demonstrate the efficacy of siRNA-mediated targeting strategies in the treatment of OA, but further work is needed to validate these findings in human joints. Meanwhile, other key targets for siRNA-mediated inhibition include the NF-κB and transforming growth factor-beta (TGF-β) pathways (inflammation), SOST (subchondral bone remodeling), hypoxia-induced factor 2a (Hif2a) (cartilage degeneration and synovitis), MMP13 (matrix catabolism) and mitochondrial dysfunction, which results in cell apoptosis [158,159,160].
Mature miRNAs are non-coding, single stranded and range from 21–24 nucleotides in length (Figure 4). miRNAs regulate gene expression through the targeting and cleavage of mRNA or via translational repression through binding interactions with the 3′untranslated region (3′ UTR) of target mRNAs [161,162]. New miRNAs are being discovered regularly and the function of these new biomolecules is under study. Currently, miRNAs are known to be involved in the regulation of cell differentiation, cell cycle progression, apoptosis, lipid metabolism, gene and protein expression and the modulation of intercellular communication in numerous cell types [163,164,165,166,167]. Given the diversity of their biological roles, it is unsurprising that aberrant miRNA expression has been linked to OA and there are many reviews that focus solely on these biomolecules. Here, we will provide a brief overview of the role of miRNAs in OA pathogenesis to provide insight into their epigenetic function (Table 1). One early study into the role of miRNAs in OA pathogenesis examined the expression patterns of miRNAs in knee cartilage and bone samples of arthroplasty patients compared cartilage from to post-mortem healthy cartilage and bone [168]. This study identified 157 miRNAs that were statistically different in the OA individuals and two specific miRNAs, miR-9 and miR-98, were subsequently identified to upregulate the expression MMP-13, IL-6 and TNFα [168,169]. miRNA-140 is another miRNA with functional roles in healthy and diseased chondrocytes. miRNA-140 is highly expressed during endochondral ossification of long bones and significantly decreased under inflammatory conditions in vitro and in OA tissues in vivo [170,171,172]. The functional role of miRNA-140 was discovered to be the inhibition of ADAMTS-5 aggrecanase expression as well as the post-translational inhibition of MMP-13 and insulin-like growth factor binding protein 5 (IGFBP-5) [171,172,173,174]. miRNAs are also capable of regulating chondrocyte anabolic expression. miRNA-148a serves dual chondroprotective roles: it inhibits chondrocyte hypertrophy and enhances Col2α1 chondrocyte deposition [175]. Recent findings demonstrate that miR-4784 enhances Col2α1 expression while simultaneously inhibiting MMP-3 to reduce ECM degradation [176,177]. Similarly, the miRNAs miR-98 and miR-181a play a role in chondrocyte homeostasis through the inhibition of BCL2 apoptosis regulator (BCL2) translation to slow the accelerated chondrocyte apoptosis seen in OA [178,179]. Conversely, miR-101 and miR-145 upregulate ECM catabolism and, when inhibited, lead to increases in SOX-9, Col2α1 and proteoglycan deposition [180].
miRNAs have also been discovered to contribute to OA synovial pathology. Examinations of synovium from a murine DMM model identified 394 differentially expressed miRNAs during post-traumatic OA development [181]. Additionally, studies of miRNA expression in human OA detected differential expression in disease chondrocytes and cartilage. These were found to have various roles in disease development such as increased inflammatory response (miRs-381a-3p, 34a, 146a, 181a), increased NF-κB signaling (miR-381a-3p), and enhanced angiogenesis (miR-125) [182,183,184,185,186]. Synovial miRNAs can also serve anti-inflammatory functions and protect against ECM degradation [187,188,189]. While many studies have focused on the miRNA contributions in chondrocyte and cartilage pathology, fewer have focused on synovial miRNA expression. Given the importance of the synovium in the onset and progression of OA, more studies are needed to fully understand the contribution of synovial miRNAs in OA and their mechanisms of action.
Long non-coding RNAs (lncRNAs) are non-coding RNAs classified by their size, being greater than 200 nucleotides in length (Figure 5). lncRNAs play a role in cellular structure integrity, transcription, splicing, translation, protein localization, cell cycle, apoptosis, stem cell pluripotency, embryonic development, immune responses and more [149,190]. Less is known about the role of lncRNAs in skeletal biology, but aberrant lncRNA expression has been implicated in the development of cancers, cardiovascular and neurodegenerative diseases and inflammatory diseases, such as OA [191,192,193,194,195]. lncRNAs, like other ncRNAs, have been linked to various aspects of OA such as chondrocyte apoptosis, ECM degradation and the maintenance of the chronic inflammatory response [191,196,197]. For example, the upregulation of lncRNAs such as HOTAIR, GAS5, H19, PMS2L2, and others, may increase mRNA expression for bone morphogenic protein-2 (BMP-2), ADAMTS5, MMP-9, and MMP-13 [198,199,200]. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is also associated with OA. MALAT1 expression is upregulated in OA cartilage and results in increased chondrocyte proliferation and the inhibition of apoptosis [201,202]. Another lncRNA, FOXD2-adjeacent opposite strand RNA 1 (FOXD2-AS1), is also upregulated in OA and enhances ECM degradation in OA via increased Toll-like receptor 4 (TRL4) expression [197,203]. A study examining differences in OA knee arthroplasty lncRNA expression identified 3007 lncRNAs were upregulated and 1707 were downregulated in comparison to normal samples [204]. These numbers indicate the breadth of lncRNA involvement in OA, for which further investigation is required.
circRNAs are novel ncRNAs that have evaded recognition until recently for a variety of reasons (Figure 5). circRNAs are separated from other RNAs by their circular shape, not by their size, and they have no definitive 3′ or 5′ ends for techniques recognizing the free RNA ends to acknowledge [205]. circRNAs are very stable molecules with half-lives of approximately 48 h [206]. circRNAs can be exonic or intronic, can be translated, and can influence transcriptional regulation through the regulation of miRNA [207]. These ncRNAs are involved in the pathogenesis of diseases such as diabetes, cancer, cardiovascular disease and OA [208]. In OA, circRNAs are known effect the proliferation and survival of chondrocytes as well as mediate cartilage metabolism and inflammation within the joint [208,209,210,211]. circRNAs often function as miRNA sponges, downregulating the expression of aggrecan and COL2 and enhancing the expression of ADAMTS-4, MMP-3, and MMP-13, thus leading to cartilage degradation [150,208]. Via miRNAs’ sponge activity, circRNAs have also been shown to lead to the degradation of the cartilage matrix [208]. However, circRNAs such as circSERPINE2 have been shown to have anabolic properties and may have the potential to be protective against OA [212]. Similarly, circCDK14 has been shown to protect ECM composition during OA by inhibiting Smad2 expression and inhibiting TGF-β signaling in chondrocytes [213].
Recent work into the mechanisms of ncRNA function have also identified that various ncRNAs can interact through a competitive endogenous RNA (ceRNA) axis that can alter the speed and severity of OA progression [214]. Through this interaction, ncRNAs can regulate the timing and expression of other ncRNA to alter cell homeostasis and disease pathology [215]. This novel pathway of cellular regulation is still poorly understood and warrants future study.
Table
Table 1. ncRNAs.
Table 1. ncRNAs.
ncRNAOA FunctionReferences
miR-9Enhance ECM degradation[171,172]
miR-98Enhance ECM degradation[171,172]
miR-140Inhibit ECM degradation[173,174,175,176,177]
miR-148aEnhanced ECM anabolism
Inhibit hypertrophy		[178]
miR-4784Enhances ECM anabolism
Inhibit ECM degradation		[179,180]
miR-98Inhibit ECM degradation
Inhibit inflammation		[171]
miR-181aInhibit ECM degradation
Inhibit inflammation		[171]
miR-101Enhance ECM degradation[183]
miR-145Enhance ECM degradation[183]
miR-381a-3pProinflammatory[185,186,187,188,189]
miR-34aProinflammatory[185,186,187,188,189]
miR-146aProinflammatory[185,186,187,188,189]
miR-181aProinflammatory[185,186,187,188,189]
circCDK14Inhibit ECM degradation[205]
miR-125Increased angiogenesis[185,186,187,188,189]
HOTAIREnhance ECM degradation[203]
GAS5Proinflammatory[202]
H19Proinflammatory[201]
MALAT1Inhibit apoptosis
Increase proliferation		[204,205]
FOXD2-AS1Enhance ECM degradation[206,207]

8. Epigenetics of Obesity

The prevalence of obesity in the general population is increasing and obesity itself is now identified as a global health problem [216]. The link between weight, physical activity levels, and OA is well established. Mechanical stressors such as joint loading are increased in obese individuals and are thought to contribute to disease onset and progression [217,218]. To help combat this process, weight loss is one lifestyle alteration commonly suggested in OA patients to reduce joint stress and stiffness [219,220,221].
However, it is not just weight itself that forms such a strong link between weight and OA. Adipose tissue is an active endocrine organ that secretes cytokines as well as adipokines, adipose-secreted proteins [222]. These secreted factors have systemic and local functions and influence insulin resistance, vascular function, renal function, β cell function, and cancer [223,224,225,226,227]. In OA, adipokines such as leptin, adiponectin, resistin, visfatin, and chemerin have been shown to be differentially expressed in the cartilage, synovium, and/or infrapatellar fat pads of OA patients and mechanistic studies have linked these molecules to cartilage and synovial inflammation, increased chondrocyte catabolism, and increased joint pain [228,229,230,231,232,233,234].
Recent studies have begun to examine the epigenetic regulation of obesity and the link with OA. For instance, the expression of two microRNAs (miR-935 and miR-4772) are statistically increased in obese patients [235]. Examinations of miRNA profiles in patients who have lost weight either by lifestyle changes or bariatric surgery have identified alterations in miRNA profiles post weight loss [236]. These findings have led some individuals to target anti-miRNA therapies for OA. Preclinical studies are now underway with several therapies showing potential [237]. One example of this is miR-146a that suppresses MMP-13 and ADAMTS-5 following IL-1 proinflammatory stimulation [238].
Other studies have examined alternative epigenetic regulators of obesity. Altered DNA and histone methylation patterns have been identified in obese individuals suffering from vascular disease, diabetes, and energy metabolism [239,240,241]. These findings, and the increasing body of work detailing age-related epigenetic changes, lend increasing support that epigenetic dysregulation contributes to OA pathology and highlight the need for further studies [242,243,244].

9. Epigenetic Regulators as Therapeutic Options

The development of therapeutic treatments to slow or prevent OA is challenging due to its multifactorial genetic involvement, the involvement of numerous tissue types, incomplete pathogenesis, and disease heterogeneity [158,245,246]. Pharmacological treatment options under development and evaluation seek to mitigate disease-associated pain and progression by targeting key proinflammatory mediators. Recent developments in the field of OA epigenetic regulation have also yielded new potential targets for OA therapeutics.
Traditionally, therapeutics have targeted the molecular pathways known to be affected in OA pathogenesis. For instance, cartilage degradation due to proteolytic enzymes have been countered with metalloproteinase and aggrecanase inhibitors and bisphosphonates have been prescribed to rebalance bone homeostasis (2). However, these therapies have had limited success due to differences in patient genetic backgrounds and the mixed effects between different joint tissues. These findings highlight the potential use of epigenetic targets for OA treatments, particularly epigenetic regulators found in all joint cell and tissue types.
One therapeutic target that shows promise is ten-eleven-translocation (TET) enzymes TET1, -2 and -3 methylcytosine dioxygenases function in DNA hydroxymethylation and have been shown to have cell-specific gene expression regulatory functions [247,248,249]. Additionally, TETs have been shown to regulate multiple OA-related anabolic (Col2α1, Acan) and catabolic (Mmp-3, Mmp-13 and Adamts-5) genes [250,251,252]. TETs are also involved in dysregulated chondrocyte homeostasis through the regulation of the Wnt and mTOR pathways [252]. A pharmacological inhibitor, 2-hydroxyglutarate, has been shown to inhibit OA development in a murine destabilization of the medial meniscus model highlighting the therapeutic potential of the molecule, but this has yet to be investigated in clinical trials [252,253]. Other molecules have also been developed that target DNA methyltransferases (DMTs) activity such as TETs. Two inhibitors, azacytidine and decitabine, have already been granted FDA approval for use in blood, colorectal, ovarian and breast cancers [231,254,255,256,257]. Based on in vitro studies, decitabine also shows potential for use in OA but no clinical trials are presently examining this role [258].
The pharmacological inhibition of polycomb recessive complexes is also currently under investigation as potential therapeutics. A small-molecule inhibitor of PRC2 complex member EZH2, EPZ005687, is under evaluation in murine OA models. The results have been mixed. Using pharmacological inhibition with this molecule, OA was inhibited following induced medial meniscectomy surgery [134]. However, the genetic ablation of EZH2 in a cartilage-specific murine model showed exacerbated OA development [135]. These findings highlight the potential of EZH2 pharmacological intervention, but caution that patient genetic background, cell-type-specific events and timing need to be further studied. Finally, other EZH2 inhibitors (such as tazemetostat, E7438, GSK126 and UNC1999) have been utilized in various cancer treatments, and it would be beneficial to test these drugs for efficacy in OA [259,260,261,262].
Histone deacetlyases (HDACs) have been a potential therapeutic option for many years now. The inhibition of these enzymes through HDACi shows potential for the inhibition of matrix catabolism and inflammation. However, an early HDAC inhibitor, Trichostatin A, failed to inhibit MMP-13 expression in human chondrocytes [107,263,264]. Interestingly, the siRNA-mediated inhibition of HDAC7 did inhibit MMP-13, demonstrating that the inhibition of specific HDACs, versus a broad-range inhibitor such as Trichostatin A, may be a more beneficial approach [107]. This hypothesis was further validated when HDAC4 inhibition with SW1353 inhibited inflammation following proinflammatory stimulation [104,265]. While continuing studies of the long-term usage of these drugs suggests HDACis have detrimental effects on the skeleton in children and adults, HDAC inhibitors have been found to be largely beneficial to the health of chondrocytes [89,266,267]. One Class III HDAC, Sirt1, has been shown to stabilize chondrocyte homeostasis and demonstrates reduced expression in OA patients [268,269,270]. Sirt1 activator, resvertol, has recently been shown to protect against cartilage damage in surgical OA murine and rat models, but human trials are still needed to test the effects in human OA [271,272,273]. To further our knowledge about HDACi in OA and towards the development of new therapeutic approaches, other specific HDAC inhibitors, including ACY-1215, RGFP966 and vorinostat, are being used in ongoing clinical and murine trials to evaluate the efficacy of these molecules alone and in combination [266,274,275].
Cell therapy is another therapeutic option gaining favor in the treatment of OA. Studies of other disease pathologies have identified that mesenchymal stem cells (MSCs) can interact with the immune system and modulate aspects of the anti-inflammatory response [276,277,278], making them of interest in the treatment of OA. Preclinical studies of intra-articular injections showed promise in animal preclinical trials and researchers are developing various biological packaging options to minimize the risks of injection site leakage and the possibility of rejection effects [279,280]. At present, several clinical trials are underway in the United States to test the efficacy of intra-articular injections of MSCs, bone marrow aspirates and platelet-rich plasma in OA treatment.
Currently no siRNA therapeutic agents are on the market or in clinical trials in the treatment of OA; however, they are on the market for other conditions such as pancreatic ductal carcinoma, Ebola virus infection, Hepatic fibrosis and others [151]. siRNAs as therapeutic options offer the benefit of high target gene specificity and the flexibility to target various aspects of the disease from chronic inflammation to matrix degradation. However, these methods do not come without their shortcomings. siRNAs are negatively charged, making it difficult for them to cross cell membranes and elicit a response. This characteristic causes difficulties in delivery and a lack of adequate volume of siRNA accessing the area of interest. Due to these difficulties, researchers are investigating different drug delivery techniques such as liposome-based, nanoparticle-based and antibody-based methods to provide better localized delivery [148]. Current siRNA targets under investigation in preclinical trials for OA include, but are not limited to, Indian hedgehog, NF-kB, yes-associated protein, hypoxia-induced factor 2 a, and matrix-degrading enzymes such as matrix metalloproteinases [158,160,281,282].
The use of miRNAs is also only in the preclinical stage, with targeting genes such as MMP-13, ADAMTS-5, vascular endothelial growth factor (VEGF), BCL2 and more being used [158,283,284]. lncRNAs have two promising therapeutic uses, as predictive biomarkers, such as HOTTIP, and potential therapies, via the downregulation of lncRNA-CIR, for example, [285,286]. Similarly, circRNAs provide potentials biomarkers, such as hsa_circ 0032131, and as potential therapies [287]. However, research into the use of lnRNAs and circRNAs in this manner is very preliminary and there is a lack of evidence of its efficacy. There is great potential for the use of siRNAs, miRNAs, lncRNAs and circRNAs in the treatment of OA; however, further investigation into the pathogenesis of OA and the use of miRNAs, siRNAs, lncRNAs and circRNAs in treatment is required.

10. Concluding Remarks

As the global population ages, the prevalence of age-related diseases, such as OA, is predicted to increase. In the United States alone, the aged population over the age of 85 years is theorized to triple by 2050 [288]. Skeletal and joint diseases such as osteoarthritis reduce mobility in affected individuals due to chronic pain and stiffness, particularly in diarthrodial joints. In this review, we have examined several known epigenetic factors that contribute to OA disease pathogenesis. The dysregulation of these epigenetic regulators contributes to all aspects of OA progression. They regulate proinflammatory cytokine and chemokine expression and secretion, the macrophage inflammatory response within synovial tissues, proteolytic enzymes that increase cartilage degradation, and even the regulation of bone cell homeostasis, which contributes to abnormal subchondral bone remodeling and the formation of osteophytes.
Currently, pharmacological and surgical interventions for OA are limited. They focus primarily on symptom management but are unable to treat the underlying causes of the disease or slow its progression. Pharmacological remedies that address epigenetic regulation offer hope more effective treatments will soon be identified.

Author Contributions

Conceptualization, F.F.S. and H.C.B.; data curation, H.C.B., A.L.A., T.K.S. and A.M.A.; writing—original draft preparation, H.C.B. and A.L.A.; writing—review and editing, H.C.B. and F.F.S.; visualization, A.L.A., T.K.S. and A.M.A.; project administration, F.F.S. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

Osteoarthritis (OA), non-coding RNAs (ncRNAs), small-interfering RNAs (siRNAs), microRNAs (miRNAs), extracellular matrix (ECM), polycomb repressive complexes (PRCs), DNA methyltransferases (DNMTs), matrix metalloproteinase (MMP), A disintegrin and metalloproteinase with thrombospondin motif 5 (ADAMTS-5), interleukin (IL), inducible nitric oxide synthase (iNOS), tumor necrosis factor-alpha (TNF-α), type-II collagen (Col2α1), aggrecan (ACAN), sclerostin (SOST), Wnt-ligand secretion mediator (WLS), single nucleotide polymorphisms (SNPs), type-11a1 collagen (COL11a1), vascular endothelial growth factor (VEGF), growth differentiation factor 5 (GDF5), small ubiquitin-like modifiers (SUMO), histone methyltransferases (HMTs), histone demethyltransferases (HDMTs), SRY-box transcription factor-9 (SOX-9), Nuclear Factor of Activated T-cells-1 (NFATC1), DOT1-like histone lysine methyltransferase (DOT1L), sirtuin 1 (SIRT1), lymphoid enhancer-binding factor 1 (LEF1), T-cell factor 1 (TCF1), wingless-type (Wnt), Runt-related transcription factor 2 (RUNX2), Indian hedgehog (IHH), histone acetyltransferases (HATs), histone deacetylases (HDACs), enhancer of Zeste 1 polycomb repressive complex subunit-1 (EZH1), enhancer of Zeste 2 polycomb repressive complex subunit-2 (EZH2), scaffold protein Zeste 12 homolog (SUZ12), nitric oxide (NO), secreted frizzle-related protein (SFRP-1), medial meniscectomy (MMx), conditional knockout (cKO), the hypoxia-inducible transcription factor 1α (Hif1α), small nucleolar RNAs (snoRNAs), small nuclear RNAs (snRNAs), long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), RNA-induced silencing complex (RISC), RNA interference (RNAi), Transforming growth factorβ-activated kinase-1 (TAK1), transforming growth factor-beta (TGF-β), the 3′untranslated region (3′ UTR), insulin like growth factor binding protein 5 (IGFBP-5), BCL2 apoptosis regulator (BCL2), bone morphogenic protein-2 (BMP-2), metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), FOXD2-adjeacent opposite strand RNA 1 (FOXD2-AS1), Toll-like receptor 4 (TRL4), competitive endogenous RNA (ceRNA), ten-eleven-translocation (TET), and mesenchymal stem cells (MSCs).

References

  1. Waddington, C.H. An Introduction to Modern Genetics; The Macmillan Company: New York, NY, USA, 1939. [Google Scholar]
  2. Greally, J.M. A user’s guide to the ambiguous word ‘epigenetics’. Nat. Rev. Mol. Cell. Biol. 2018, 19, 207–208. [Google Scholar] [CrossRef] [PubMed]
  3. Cavalli, G.; Heard, E. Advances in epigenetics link genetics to the environment and disease. Nature 2019, 571, 489–499. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  4. Friedrich, T.; Faivre, L.; Baurle, I.; Schubert, D. Chromatin-based mechanisms of temperature memory in plants. Plant Cell Environ. 2019, 42, 762–770. [Google Scholar] [CrossRef] [PubMed]
  5. Pagiatakis, C.; Musolino, E.; Gornati, R.; Bernardini, G.; Papait, R. Epigenetics of aging and disease: A brief overview. Aging Clin. Exp. Res. 2021, 33, 737–745. [Google Scholar] [CrossRef] [Green Version]
  6. De Rubeis, S.; He, X.; Goldberg, A.P.; Poultney, C.S.; Samocha, K.; Cicek, A.E.; Kou, Y.; Liu, L.; Fromer, M.; Walker, S.; et al. Synaptic, transcriptional and chromatin genes disrupted in autism. Nature 2014, 515, 209–215. [Google Scholar] [CrossRef]
  7. Kleer, C.G.; Cao, Q.; Varambally, S.; Shen, R.; Ota, I.; Tomlins, S.A.; Ghosh, D.; Sewalt, R.G.; Otte, A.P.; Hayes, D.F.; et al. EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proc. Natl. Acad. Sci. USA 2003, 100, 11606–11611. [Google Scholar] [CrossRef] [Green Version]
  8. Naylor, R.M.; Baker, D.J.; van Deursen, J.M. Senescent cells: A novel therapeutic target for aging and age-related diseases. Clin. Pharmacol. Ther. 2013, 93, 105–116. [Google Scholar] [CrossRef]
  9. Tiffon, C. The Impact of Nutrition and Environmental Epigenetics on Human Health and Disease. Int. J. Mol. Sci. 2018, 19, 3425. [Google Scholar] [CrossRef] [Green Version]
  10. Lind, L.; Ingelsson, E.; Sundstrom, J.; Siegbahn, A.; Lampa, E. Methylation-based estimated biological age and cardiovascular disease. Eur. J. Clin. Investig. 2018, 48, e12872. [Google Scholar] [CrossRef]
  11. Kato, M.; Natarajan, R. Epigenetics and epigenomics in diabetic kidney disease and metabolic memory. Nat. Rev. Nephrol. 2019, 15, 327–345. [Google Scholar] [CrossRef]
  12. Qiu, C.; Huang, S.; Park, J.; Park, Y.; Ko, Y.A.; Seasock, M.J.; Bryer, J.S.; Xu, X.X.; Song, W.C.; Palmer, M.; et al. Renal compartment-specific genetic variation analyses identify new pathways in chronic kidney disease. Nat. Med. 2018, 24, 1721–1731. [Google Scholar] [CrossRef] [PubMed]
  13. Loeser, R.F.; Collins, J.A.; Diekman, B.O. Ageing and the pathogenesis of osteoarthritis. Nat. Rev. Rheumatol. 2016, 12, 412–420. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  14. Harrell, C.R.; Markovic, B.S.; Fellabaum, C.; Arsenijevic, A.; Volarevic, V. Mesenchymal stem cell-based therapy of osteoarthritis: Current knowledge and future perspectives. Biomed. Pharmacother. 2019, 109, 2318–2326. [Google Scholar] [CrossRef] [PubMed]
  15. Musumeci, G.; Aiello, F.C.; Szychlinska, M.A.; Di Rosa, M.; Castrogiovanni, P.; Mobasheri, A. Osteoarthritis in the XXIst century: Risk factors and behaviours that influence disease onset and progression. Int. J. Mol. Sci. 2015, 16, 6093–6112. [Google Scholar] [CrossRef]
  16. Hawker, G.A. Osteoarthritis is a serious disease. Clin. Exp. Rheumatol. 2019, 37, S3–S6. [Google Scholar]
  17. Aburto, J.M.; Villavicencio, F.; Basellini, U.; Kjaergaard, S.; Vaupel, J.W. Dynamics of life expectancy and life span equality. Proc. Natl. Acad. Sci. USA 2020, 117, 5250–5259. [Google Scholar] [CrossRef] [Green Version]
  18. Rice, S.J.; Beier, F.; Young, D.A.; Loughlin, J. Interplay between genetics and epigenetics in osteoarthritis. Nat. Rev. Rheumatol. 2020, 16, 268–281. [Google Scholar] [CrossRef]
  19. Chen, Y.; Jiang, W.; Yong, H.; He, M.; Yang, Y.; Deng, Z.; Li, Y. Macrophages in osteoarthritis: Pathophysiology and therapeutics. Am. J. Transl. Res. 2020, 12, 261–268. [Google Scholar]
  20. Jang, S.; Lee, K.; Ju, J.H. Recent Updates of Diagnosis, Pathophysiology, and Treatment on Osteoarthritis of the Knee. Int. J. Mol. Sci. 2021, 22, 2619. [Google Scholar] [CrossRef]
  21. Loeser, R.F.; Goldring, S.R.; Scanzello, C.R.; Goldring, M.B. Osteoarthritis: A disease of the joint as an organ. Arthritis Rheum. 2012, 64, 1697–1707. [Google Scholar] [CrossRef] [Green Version]
  22. Man, G.; Mologhianu, G. Osteoarthritis pathogenesis–a complex process that involves the entire joint. J. Med. Life 2014, 7, 37. [Google Scholar] [PubMed]
  23. Di Laura Frattura, G.; Filardo, G.; Giunchi, D.; Fusco, A.; Zaffagnini, S.; Candrian, C. Risk of falls in patients with knee osteoarthritis undergoing total knee arthroplasty: A systematic review and best evidence synthesis. J. Orthop. 2018, 15, 903–908. [Google Scholar] [CrossRef] [PubMed]
  24. He, Y.; Li, Z.; Alexander, P.G.; Ocasio-Nieves, B.D.; Yocum, L.; Lin, H.; Tuan, R.S. Pathogenesis of Osteoarthritis: Risk Factors, Regulatory Pathways in Chondrocytes, and Experimental Models. Biology 2020, 9, 194. [Google Scholar] [CrossRef]
  25. Szilagyi, I.A.; Waarsing, J.H.; Schiphof, D.; van Meurs, J.B.J.; Bierma-Zeinstra, S.M.A. Towards sex-specific osteoarthritis risk models: Evaluation of risk factors for knee osteoarthritis in males and females. Rheumatology 2021, 61, 648–657. [Google Scholar] [CrossRef] [PubMed]
  26. Kundu, S.; Ashinsky, B.G.; Bouhrara, M.; Dam, E.B.; Demehri, S.; Shifat, E.R.M.; Spencer, R.G.; Urish, K.L.; Rohde, G.K. Enabling early detection of osteoarthritis from presymptomatic cartilage texture maps via transport-based learning. Proc. Natl. Acad. Sci. USA 2020, 117, 24709–24719. [Google Scholar] [CrossRef] [PubMed]
  27. Bedson, J.; Croft, P.R. The discordance between clinical and radiographic knee osteoarthritis: A systematic search and summary of the literature. BMC Musculoskelet. Disord. 2008, 9, 116. [Google Scholar] [CrossRef] [Green Version]
  28. Katz, J.N.; Earp, B.E.; Gomoll, A.H. Surgical management of osteoarthritis. Arthritis Care Res. 2010, 62, 1220–1228. [Google Scholar] [CrossRef]
  29. Ronn, K.; Reischl, N.; Gautier, E.; Jacobi, M. Current surgical treatment of knee osteoarthritis. Arthritis 2011, 2011, 454873. [Google Scholar] [CrossRef] [Green Version]
  30. Singh, P.; Marcu, K.B.; Goldring, M.B.; Otero, M. Phenotypic instability of chondrocytes in osteoarthritis: On a path to hypertrophy. Ann. N. Y. Acad. Sci. 2019, 1442, 17–34. [Google Scholar] [CrossRef]
  31. Van der Kraan, P.; Matta, C.; Mobasheri, A. Age-Related Alterations in Signaling Pathways in Articular Chondrocytes: Implications for the Pathogenesis and Progression of Osteoarthritis—A Mini-Review. Gerontology 2017, 63, 29–35. [Google Scholar] [CrossRef] [Green Version]
  32. Zengini, E.; Hatzikotoulas, K.; Tachmazidou, I.; Steinberg, J.; Hartwig, F.P.; Southam, L.; Hackinger, S.; Boer, C.G.; Styrkarsdottir, U.; Gilly, A.; et al. Genome-wide analyses using UK Biobank data provide insights into the genetic architecture of osteoarthritis. Nat. Genet. 2018, 50, 549–558. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  33. Gallagher, M.D.; Chen-Plotkin, A.S. The Post-GWAS Era: From Association to Function. Am. J. Hum. Genet. 2018, 102, 717–730. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  34. Kim, H.; Kang, D.; Cho, Y.; Kim, J.-H. Epigenetic regulation of chondrocyte catabolism and anabolism in osteoarthritis. Mol. Cells 2015, 38, 677. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  35. Gujar, H.; Weisenberger, D.J.; Liang, G. The Roles of Human DNA Methyltransferases and Their Isoforms in Shaping the Epigenome. Genes 2019, 10, 172. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  36. Takebayashi, S.I.; Ryba, T.; Wimbish, K.; Hayakawa, T.; Sakaue, M.; Kuriya, K.; Takahashi, S.; Ogata, S.; Hiratani, I.; Okumura, K.; et al. The Temporal Order of DNA Replication Shaped by Mammalian DNA Methyltransferases. Cells 2021, 10, 266. [Google Scholar] [CrossRef] [PubMed]
  37. Maunakea, A.K.; Nagarajan, R.P.; Bilenky, M.; Ballinger, T.J.; D’Souza, C.; Fouse, S.D.; Johnson, B.E.; Hong, C.; Nielsen, C.; Zhao, Y.; et al. Conserved role of intragenic DNA methylation in regulating alternative promoters. Nature 2010, 466, 253–257. [Google Scholar] [CrossRef] [PubMed]
  38. Fathollahi, A.; Aslani, S.; Jamshidi, A.; Mahmoudi, M. Epigenetics in osteoarthritis: Novel spotlight. J. Cell Physiol. 2019, 234, 12309–12324. [Google Scholar] [CrossRef]
  39. Izda, V.; Martin, J.; Sturdy, C.; Jeffries, M.A. DNA methylation and noncoding RNA in OA: Recent findings and methodological advances. Osteoarthr. Cartil. Open 2021, 3, 100208. [Google Scholar] [CrossRef]
  40. Reynard, L.N. Analysis of genetics and DNA methylation in osteoarthritis: What have we learnt about the disease? Semin. Cell Dev. Biol. 2017, 62, 57–66. [Google Scholar] [CrossRef] [Green Version]
  41. Simon, T.C.; Jeffries, M.A. The Epigenomic Landscape in Osteoarthritis. Curr. Rheumatol. Rep. 2017, 19, 30. [Google Scholar] [CrossRef]
  42. De Andres, M.C.; Imagawa, K.; Hashimoto, K.; Gonzalez, A.; Roach, H.I.; Goldring, M.B.; Oreffo, R.O. Loss of methylation in CpG sites in the NF-kappaB enhancer elements of inducible nitric oxide synthase is responsible for gene induction in human articular chondrocytes. Arthritis Rheum. 2013, 65, 732–742. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  43. Hashimoto, K.; Otero, M.; Imagawa, K.; De Andrés, M.C.; Coico, J.M.; Roach, H.I.; Oreffo, R.O.; Marcu, K.B.; Goldring, M.B. Regulated transcription of human matrix metalloproteinase 13 (MMP13) and interleukin-1β (IL1B) genes in chondrocytes depends on methylation of specific proximal promoter CpG sites. J. Biol. Chem. 2013, 288, 10061–10072. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  44. Saito, T.; Fukai, A.; Mabuchi, A.; Ikeda, T.; Yano, F.; Ohba, S.; Nishida, N.; Akune, T.; Yoshimura, N.; Nakagawa, T. Transcriptional regulation of endochondral ossification by HIF-2α during skeletal growth and osteoarthritis development. Nat. Med. 2010, 16, 678–686. [Google Scholar] [CrossRef] [PubMed]
  45. Roach, H.I.; Yamada, N.; Cheung, K.S.; Tilley, S.; Clarke, N.M.; Oreffo, R.O.; Kokubun, S.; Bronner, F. Association between the abnormal expression of matrix-degrading enzymes by human osteoarthritic chondrocytes and demethylation of specific CpG sites in the promoter regions. Arthritis Rheum. 2005, 52, 3110–3124. [Google Scholar] [CrossRef] [PubMed]
  46. Kim, K.I.; Park, Y.S.; Im, G.I. Changes in the epigenetic status of the SOX-9 promoter in human osteoarthritic cartilage. J. Bone Miner. Res. 2013, 28, 1050–1060. [Google Scholar] [CrossRef]
  47. Imagawa, K.; De Andrés, M.C.; Hashimoto, K.; Itoi, E.; Otero, M.; Roach, H.I.; Goldring, M.B.; Oreffo, R.O. Association of reduced type IX collagen gene expression in human osteoarthritic chondrocytes with epigenetic silencing by DNA hypermethylation. Arthritis Rheumatol. 2014, 66, 3040–3051. [Google Scholar] [CrossRef] [Green Version]
  48. Papathanasiou, I.; Kostopoulou, F.; Malizos, K.N.; Tsezou, A. DNA methylation regulates sclerostin (SOST) expression in osteoarthritic chondrocytes by bone morphogenetic protein 2 (BMP-2) induced changes in Smads binding affinity to the CpG region of SOST promoter. Arthritis Res. Ther. 2015, 17, 1–10. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  49. Rodriguez-Fontenla, C.; Calaza, M.; Evangelou, E.; Valdes, A.M.; Arden, N.; Blanco, F.J.; Carr, A.; Chapman, K.; Deloukas, P.; Doherty, M. Assessment of osteoarthritis candidate genes in a meta-analysis of nine genome-wide association studies. Arthritis Rheumatol. 2014, 66, 940–949. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  50. Valdes, A.M.; Evangelou, E.; Kerkhof, H.J.; Tamm, A.; Doherty, S.A.; Kisand, K.; Tamm, A.; Kerna, I.; Uitterlinden, A.; Hofman, A. The GDF5 rs143383 polymorphism is associated with osteoarthritis of the knee with genome-wide statistical significance. Ann. Rheum. Dis. 2011, 70, 873–875. [Google Scholar] [CrossRef] [Green Version]
  51. Miyamoto, Y.; Mabuchi, A.; Shi, D.; Kubo, T.; Takatori, Y.; Saito, S.; Fujioka, M.; Sudo, A.; Uchida, A.; Yamamoto, S. A functional polymorphism in the 5′ UTR of GDF5 is associated with susceptibility to osteoarthritis. Nat. Genet. 2007, 39, 529–533. [Google Scholar] [CrossRef]
  52. Bomer, N.; den Hollander, W.; Ramos, Y.F.; Bos, S.D.; van der Breggen, R.; Lakenberg, N.; Pepers, B.A.; van Eeden, A.E.; Darvishan, A.; Tobi, E.W.; et al. Underlying molecular mechanisms of DIO2 susceptibility in symptomatic osteoarthritis. Ann. Rheum. Dis. 2015, 74, 1571–1579. [Google Scholar] [CrossRef] [Green Version]
  53. Rushton, M.D.; Reynard, L.N.; Young, D.A.; Shepherd, C.; Aubourg, G.; Gee, F.; Darlay, R.; Deehan, D.; Cordell, H.J.; Loughlin, J. Methylation quantitative trait locus analysis of osteoarthritis links epigenetics with genetic risk. Hum. Mol. Genet. 2015, 24, 7432–7444. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  54. Meulenbelt, I.; Chapman, K.; Dieguez-Gonzalez, R.; Shi, D.; Tsezou, A.; Dai, J.; Malizos, K.N.; Kloppenburg, M.; Carr, A.; Nakajima, M. Large replication study and meta-analyses of DVWA as an osteoarthritis susceptibility locus in European and Asian populations. Hum. Mol. Genet. 2009, 18, 1518–1523. [Google Scholar] [CrossRef] [PubMed]
  55. Bos, S.D.; Slagboom, P.E.; Meulenbelt, I. New insights into osteoarthritis: Early developmental features of an ageing-related disease. Curr. Opin. Rheumatol. 2008, 20, 553–559. [Google Scholar] [CrossRef]
  56. Lindner, C.; Thiagarajah, S.; Wilkinson, J.M.; Panoutsopoulou, K.; Day-Williams, A.G.; Consortium, A.; Cootes, T.F.; Wallis, G.A.; Loughlin, J.; Arden, N. Investigation of association between hip osteoarthritis susceptibility loci and radiographic proximal femur shape. Arthritis Rheumatol. 2015, 67, 2076–2084. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  57. Reynard, L.N.; Loughlin, J. Insights from human genetic studies into the pathways involved in osteoarthritis. Nat. Rev. Rheumatol. 2013, 9, 573–583. [Google Scholar] [CrossRef] [PubMed]
  58. Park, S.Y.; Kim, J.S. A short guide to histone deacetylases including recent progress on class II enzymes. Exp. Mol. Med. 2020, 52, 204–212. [Google Scholar] [CrossRef]
  59. Bartova, E.; Krejci, J.; Harnicarova, A.; Galiova, G.; Kozubek, S. Histone modifications and nuclear architecture: A review. J. Histochem. Cytochem. 2008, 56, 711–721. [Google Scholar] [CrossRef] [Green Version]
  60. Bannister, A.J.; Kouzarides, T. Regulation of chromatin by histone modifications. Cell Res. 2011, 21, 381–395. [Google Scholar] [CrossRef]
  61. Ryu, H.Y.; Hochstrasser, M. Histone sumoylation and chromatin dynamics. Nucleic Acids Res. 2021, 49, 6043–6052. [Google Scholar] [CrossRef]
  62. Aquila, L.; Atanassov, B.S. Regulation of Histone Ubiquitination in Response to DNA Double Strand Breaks. Cells 2020, 9, 1699. [Google Scholar] [CrossRef] [PubMed]
  63. Hananya, N.; Daley, S.K.; Bagert, J.D.; Muir, T.W. Synthesis of ADP-Ribosylated Histones Reveals Site-Specific Impacts on Chromatin Structure and Function. J. Am. Chem. Soc. 2021, 143, 10847–10852. [Google Scholar] [CrossRef] [PubMed]
  64. Dieker, J.; Muller, S. Epigenetic histone code and autoimmunity. Clin. Rev. Allergy Immunol. 2010, 39, 78–84. [Google Scholar] [CrossRef] [PubMed]
  65. Zhang, M.; Theleman, J.L.; Lygrisse, K.A.; Wang, J. Epigenetic Mechanisms Underlying the Aging of Articular Cartilage and Osteoarthritis. Gerontology 2019, 65, 387–396. [Google Scholar] [CrossRef] [PubMed]
  66. Raman, S.; FitzGerald, U.; Murphy, J.M. Interplay of Inflammatory Mediators with Epigenetics and Cartilage Modifications in Osteoarthritis. Front. Bioeng. Biotechnol. 2018, 6, 22. [Google Scholar] [CrossRef] [PubMed]
  67. Shi, Y.; Lan, F.; Matson, C.; Mulligan, P.; Whetstine, J.R.; Cole, P.A.; Casero, R.A.; Shi, Y. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 2004, 119, 941–953. [Google Scholar] [CrossRef] [Green Version]
  68. Whetstine, J.R.; Nottke, A.; Lan, F.; Huarte, M.; Smolikov, S.; Chen, Z.; Spooner, E.; Li, E.; Zhang, G.; Colaiacovo, M.; et al. Reversal of histone lysine trimethylation by the JMJD2 family of histone demethylases. Cell 2006, 125, 467–481. [Google Scholar] [CrossRef] [Green Version]
  69. He, J.; Cao, W.; Azeem, I.; Shao, Z. Epigenetics of osteoarthritis: Histones and TGF-beta1. Clin. Chim. Acta 2020, 510, 593–598. [Google Scholar] [CrossRef]
  70. Portela, A.; Esteller, M. Epigenetic modifications and human disease. Nat. Biotechnol. 2010, 28, 1057–1068. [Google Scholar] [CrossRef]
  71. El Mansouri, F.E.; Chabane, N.; Zayed, N.; Kapoor, M.; Benderdour, M.; Martel-Pelletier, J.; Pelletier, J.P.; Duval, N.; Fahmi, H. Contribution of H3K4 methylation by SET-1A to interleukin-1-induced cyclooxygenase 2 and inducible nitric oxide synthase expression in human osteoarthritis chondrocytes. Arthritis Rheum. 2011, 63, 168–179. [Google Scholar] [CrossRef]
  72. Ukita, M.M.; Kenji, M.; Tamura, M.; Yamaguchi, T. Histone H3K9 methylation is involved in temporomandicular joint osteoarthritis. Int. J. Mol. Med. 2020, 45, 607–614. [Google Scholar] [PubMed]
  73. Lefebvre, V.; Angelozzi, M.; Haseeb, A. SOX9 in cartilage development and disease. Curr. Opin. Cell Biol. 2019, 61, 39–47. [Google Scholar] [CrossRef] [PubMed]
  74. Lefebvre, V.; Dvir-Ginzberg, M. SOX9 and the many facets of its regulation in the chondrocyte lineage. Connect. Tissue Res. 2017, 58, 2–14. [Google Scholar] [CrossRef] [PubMed]
  75. Lee, J.S.; Im, G.I. SOX trio decrease in the articular cartilage with the advancement of osteoarthritis. Connect. Tissue Res. 2011, 52, 496–502. [Google Scholar] [CrossRef]
  76. Rodova, M.; Lu, Q.H.; Li, Y.; Woodbury, B.G.; Crist, J.D.; Gardner, B.M.; Yost, J.G.; Zhong, X.B.; Anderson, H.C.; Wang, J.X. Nfat1 Regulates Adult Articular Chondrocyte Function Through Its Age-Dependent Expression Mediated by Epigenetic Histone Methylation. J. Bone Miner. Res. 2011, 26, 1974–1986. [Google Scholar] [CrossRef] [Green Version]
  77. Wang, J.; Rodova, M.; Lu, Q.; Woodbury, B.; Zhong, X.B.; Anderson, H. Nfat1 regulates adult articular chondrocyte function through its age-dependent expression mediated by epigenetic histone methylation. Bone 2011, 48, S14–S142. [Google Scholar] [CrossRef]
  78. Castano Betancourt, M.C.; Cailotto, F.; Kerkhof, H.J.; Cornelis, F.M.; Doherty, S.A.; Hart, D.J.; Hofman, A.; Luyten, F.P.; Maciewicz, R.A.; Mangino, M.; et al. Genome-wide association and functional studies identify the DOT1L gene to be involved in cartilage thickness and hip osteoarthritis. Proc. Natl. Acad. Sci. USA 2012, 109, 8218–8223. [Google Scholar] [CrossRef] [Green Version]
  79. Nguyen, A.T.; Zhang, Y. The diverse functions of Dot1 and H3K79 methylation. Gene Dev. 2011, 25, 1345–1358. [Google Scholar] [CrossRef] [Green Version]
  80. Wang, T.; Hao, Z.; Liu, C.; Yuan, L.; Li, L.; Yin, M.; Li, Q.; Qi, Z.; Wang, Z. LEF1 mediates osteoarthritis progression through circRNF121/miR-665/MYD88 axis via NF-small ka, CyrillicB signaling pathway. Cell Death Dis. 2020, 11, 598. [Google Scholar] [CrossRef]
  81. Neefjes, M.; van Caam, A.P.M.; van der Kraan, P.M. Transcription Factors in Cartilage Homeostasis and Osteoarthritis. Biology 2020, 9, 290. [Google Scholar] [CrossRef]
  82. Lietman, C.; Wu, B.; Lechner, S.; Shinar, A.; Sehgal, M.; Rossomacha, E.; Datta, P.; Sharma, A.; Gandhi, R.; Kapoor, M.; et al. Inhibition of Wnt/beta-catenin signaling ameliorates osteoarthritis in a murine model of experimental osteoarthritis. JCI Insight 2018, 3, e96308. [Google Scholar] [CrossRef] [PubMed]
  83. Cornelis, F.M.F.; de Roover, A.; Storms, L.; Hens, A.; Lories, R.J.; Monteagudo, S. Increased susceptibility to develop spontaneous and post-traumatic osteoarthritis in Dot1l-deficient mice. Osteoarthr. Cartil. 2019, 27, 513–525. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  84. Dai, J.; Yu, D.; Wang, Y.; Chen, Y.; Sun, H.; Zhang, X.; Zhu, S.; Pan, Z.; Heng, B.C.; Zhang, S. Kdm6b regulates cartilage development and homeostasis through anabolic metabolism. Ann. Rheum. Dis. 2017, 76, 1295–1303. [Google Scholar] [CrossRef] [PubMed]
  85. Zhang, F.; Xu, L.; Xu, L.; Xu, Q.; Li, D.; Yang, Y.; Karsenty, G.; Chen, C.D. JMJD3 promotes chondrocyte proliferation and hypertrophy during endochondral bone formation in mice. J. Mol. Cell Biol. 2015, 7, 23–34. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  86. Tetsunaga, T.; Nishida, K.; Furumatsu, T.; Naruse, K.; Hirohata, S.; Yoshida, A.; Saito, T.; Ozaki, T. Regulation of mechanical stress-induced MMP-13 and ADAMTS-5 expression by RUNX-2 transcriptional factor in SW1353 chondrocyte-like cells. Osteoarthr. Cartil. 2011, 19, 222–232. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  87. Carpio, L.R.; Westendorf, J.J. Histone Deacetylases in Cartilage Homeostasis and Osteoarthritis. Curr. Rheumatol. Rep. 2016, 18, 52. [Google Scholar] [CrossRef]
  88. Huber, L.C.; Brock, M.; Hemmatazad, H.; Giger, O.T.; Moritz, F.; Trenkmann, M.; Distler, J.H.; Gay, R.E.; Kolling, C.; Moch, H.; et al. Histone deacetylase/acetylase activity in total synovial tissue derived from rheumatoid arthritis and osteoarthritis patients. Arthritis Rheum. 2007, 56, 1087–1093. [Google Scholar] [CrossRef]
  89. Zhang, H.; Ji, L.; Yang, Y.; Zhang, X.; Gang, Y.; Bai, L. The Role of HDACs and HDACi in Cartilage and Osteoarthritis. Front. Cell Dev. Biol. 2020, 8, 560117. [Google Scholar] [CrossRef]
  90. Li, Y.; Wen, H.; Xi, Y.; Tanaka, K.; Wang, H.; Peng, D.; Ren, Y.; Jin, Q.; Dent, S.Y.; Li, W.; et al. AF9 YEATS domain links histone acetylation to DOT1L-mediated H3K79 methylation. Cell 2014, 159, 558–571. [Google Scholar] [CrossRef] [Green Version]
  91. Choudhary, C.; Kumar, C.; Gnad, F.; Nielsen, M.L.; Rehman, M.; Walther, T.C.; Olsen, J.V.; Mann, M. Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science 2009, 325, 834–840. [Google Scholar] [CrossRef] [Green Version]
  92. Glozak, M.A.; Sengupta, N.; Zhang, X.; Seto, E. Acetylation and deacetylation of non-histone proteins. Gene 2005, 363, 15–23. [Google Scholar] [CrossRef]
  93. Jesko, H.; Strosznajder, R.P. Sirtuins and their interactions with transcription factors and poly(ADP-ribose) polymerases. Folia Neuropathol. 2016, 54, 212–233. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  94. Parra, M.; Herrera, D.; Calvo-Calle, J.M.; Stern, L.J.; Parra-Lopez, C.A.; Butcher, E.; Franco, M.; Angel, J. Circulating human rotavirus specific CD4 T cells identified with a class II tetramer express the intestinal homing receptors alpha4beta7 and CCR9. Virology 2014, 452–453, 191–201. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  95. Reichert, N.; Choukrallah, M.A.; Matthias, P. Multiple roles of class I HDACs in proliferation, differentiation, and development. Cell Mol. Life Sci. 2012, 69, 2173–2187. [Google Scholar] [CrossRef] [Green Version]
  96. Bhaskara, S.; Chyla, B.J.; Amann, J.M.; Knutson, S.K.; Cortez, D.; Sun, Z.W.; Hiebert, S.W. Deletion of histone deacetylase 3 reveals critical roles in S phase progression and DNA damage control. Mol. Cell 2008, 30, 61–72. [Google Scholar] [CrossRef] [Green Version]
  97. Haberland, M.; Montgomery, R.L.; Olson, E.N. The many roles of histone deacetylases in development and physiology: Implications for disease and therapy. Nat. Rev. Genet. 2009, 10, 32–42. [Google Scholar] [CrossRef]
  98. Fischle, W.; Dequiedt, F.; Hendzel, M.J.; Guenther, M.G.; Lazar, M.A.; Voelter, W.; Verdin, E. Enzymatic activity associated with class II HDACs is dependent on a multiprotein complex containing HDAC3 and SMRT/N-CoR. Mol. Cell 2002, 9, 45–57. [Google Scholar] [CrossRef] [Green Version]
  99. Verdin, E.; Dequiedt, F.; Kasler, H.G. Class II histone deacetylases: Versatile regulators. Trends Genet. 2003, 19, 286–293. [Google Scholar] [CrossRef] [Green Version]
  100. Aman, Y.; Schmauck-Medina, T.; Hansen, M.; Morimoto, R.I.; Simon, A.K.; Bjedov, I.; Palikaras, K.; Simonsen, A.; Johansen, T.; Tavernarakis, N.; et al. Autophagy in healthy aging and disease. Nat. Aging 2021, 1, 634–650. [Google Scholar] [CrossRef]
  101. Li, Q.; Cheng, J.C.; Jiang, Q.; Lee, W.Y. Role of sirtuins in bone biology: Potential implications for novel therapeutic strategies for osteoporosis. Aging Cell 2021, 20, e13301. [Google Scholar] [CrossRef]
  102. Hong, S.; Derfoul, A.; Pereira-Mouries, L.; Hall, D.J. A novel domain in histone deacetylase 1 and 2 mediates repression of cartilage-specific genes in human chondrocytes. FASEB J. 2009, 23, 3539–3552. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  103. Liu, C.J.; Prazak, L.; Fajardo, M.; Yu, S.; Tyagi, N.; Di Cesare, P.E. Leukemia/lymphoma-related factor, a POZ domain-containing transcriptional repressor, interacts with histone deacetylase-1 and inhibits cartilage oligomeric matrix protein gene expression and chondrogenesis. J. Biol. Chem. 2004, 279, 47081–47091. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  104. Cao, K.; Wei, L.; Zhang, Z.; Guo, L.; Zhang, C.; Li, Y.; Sun, C.; Sun, X.; Wang, S.; Li, P.; et al. Decreased histone deacetylase 4 is associated with human osteoarthritis cartilage degeneration by releasing histone deacetylase 4 inhibition of runt-related transcription factor-2 and increasing osteoarthritis-related genes: A novel mechanism of human osteoarthritis cartilage degeneration. Arthritis Res. Ther. 2014, 16, 491. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  105. Liao, L.; Zhang, S.; Gu, J.; Takarada, T.; Yoneda, Y.; Huang, J.; Zhao, L.; Oh, C.D.; Li, J.; Wang, B.; et al. Deletion of Runx2 in Articular Chondrocytes Decelerates the Progression of DMM-Induced Osteoarthritis in Adult Mice. Sci. Rep. 2017, 7, 2371. [Google Scholar] [CrossRef] [PubMed]
  106. Zhao, W.; Zhang, S.; Wang, B.; Huang, J.; Lu, W.W.; Chen, D. Runx2 and microRNA regulation in bone and cartilage diseases. Ann. N. Y. Acad. Sci. 2016, 1383, 80–87. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  107. Higashiyama, R.; Miyaki, S.; Yamashita, S.; Yoshitaka, T.; Lindman, G.; Ito, Y.; Sasho, T.; Takahashi, K.; Lotz, M.; Asahara, H. Correlation between MMP-13 and HDAC7 expression in human knee osteoarthritis. Mod. Rheumatol. 2010, 20, 11–17. [Google Scholar] [CrossRef]
  108. Wu, Y.; Chen, L.; Wang, Y.; Li, W.; Lin, Y.; Yu, D.; Zhang, L.; Li, F.; Pan, Z. Overexpression of Sirtuin 6 suppresses cellular senescence and NF-kappaB mediated inflammatory responses in osteoarthritis development. Sci. Rep. 2015, 5, 17602. [Google Scholar] [CrossRef]
  109. Abed, É.; Couchourel, D.; Delalandre, A.; Duval, N.; Pelletier, J.-P.; Martel-Pelletier, J.; Lajeunesse, D. Low sirtuin 1 levels in human osteoarthritis subchondral osteoblasts lead to abnormal sclerostin expression which decreases Wnt/β-catenin activity. Bone 2014, 59, 28–36. [Google Scholar] [CrossRef]
  110. Dvir-Ginzberg, M.; Gagarina, V.; Lee, E.-J.; Hall, D.J. Regulation of cartilage-specific gene expression in human chondrocytes by SirT1 and nicotinamide phosphoribosyltransferase. J. Biol. Chem. 2008, 283, 36300–36310. [Google Scholar] [CrossRef] [Green Version]
  111. Bradley, E.W.; Carpio, L.R.; Olson, E.N.; Westendorf, J.J. Histone deacetylase 7 (Hdac7) suppresses chondrocyte proliferation and beta-catenin activity during endochondral ossification. J. Biol. Chem. 2015, 290, 118–126. [Google Scholar] [CrossRef] [Green Version]
  112. Carpio, L.R.; Bradley, E.W.; McGee-Lawrence, M.E.; Weivoda, M.M.; Poston, D.D.; Dudakovic, A.; Xu, M.; Tchkonia, T.; Kirkland, J.L.; van Wijnen, A.J.; et al. Histone deacetylase 3 supports endochondral bone formation by controlling cytokine signaling and matrix remodeling. Sci. Signal. 2016, 9, ra79. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  113. Goldring, S.R.; Goldring, M.B. The role of cytokines in cartilage matrix degeneration in osteoarthritis. Clin. Orthop. Relat. Res. 2004, 427, S27–S36. [Google Scholar] [CrossRef] [PubMed]
  114. Sakao, K.; Takahashi, K.A.; Arai, Y.; Saito, M.; Honjo, K.; Hiraoka, N.; Asada, H.; Shin-Ya, M.; Imanishi, J.; Mazda, O. Osteoblasts derived from osteophytes produce interleukin-6, interleukin-8, and matrix metalloproteinase-13 in osteoarthritis. J. Bone Miner. Metab. 2009, 27, 412–423. [Google Scholar] [CrossRef] [PubMed]
  115. Yang, F.; Zhou, S.; Wang, C.; Huang, Y.; Li, H.; Wang, Y.; Zhu, Z.; Tang, J.; Yan, M. Epigenetic modifications of interleukin-6 in synovial fibroblasts from osteoarthritis patients. Sci. Rep. 2017, 7, 73592. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  116. Cochran, A.G. Chapter 5—Structure and Biochemistry of the Polycomb Repressive Complex 1 Ubiquitin Ligase Module. In Polycomb Group Proteins; Pirrotta, V., Ed.; Academic Press: Cambridge, MA, USA, 2017; pp. 81–110. [Google Scholar]
  117. Marchesi, I.; Giordano, A.; Bagella, L. Roles of enhancer of zeste homolog 2: From skeletal muscle differentiation to rhabdomyosarcoma carcinogenesis. Cell Cycle 2014, 13, 516–527. [Google Scholar] [CrossRef] [Green Version]
  118. Golbabapour, S.; Abdulla, M.A.; Hajrezaei, M. A concise review on epigenetic regulation: Insight into molecular mechanisms. Int. J. Mol. Sci. 2011, 12, 8661–8694. [Google Scholar] [CrossRef]
  119. Wang, W.; Qin, J.J.; Voruganti, S.; Nag, S.; Zhou, J.; Zhang, R. Polycomb Group (PcG) Proteins and Human Cancers: Multifaceted Functions and Therapeutic Implications. Med. Res. Rev. 2015, 35, 1220–1267. [Google Scholar] [CrossRef] [Green Version]
  120. Yuen, R.K.C.; Neumann, S.M.A.; Fok, A.K.; Peñaherrera, M.S.; McFadden, D.E.; Robinson, W.P.; Kobor, M.S. Extensive epigenetic reprogramming in human somatic tissues between fetus and adult. Epigenet. Chromatin 2011, 4, 7. [Google Scholar] [CrossRef] [Green Version]
  121. Tamburri, S.; Lavarone, E.; Fernández-Pérez, D.; Conway, E.; Zanotti, M.; Manganaro, D.; Pasini, D. Histone H2AK119 Mono-Ubiquitination Is Essential for Polycomb-Mediated Transcriptional Repression. Mol. Cell 2020, 77, 840–856.e845. [Google Scholar] [CrossRef] [Green Version]
  122. Surface, L.E.; Thornton, S.R.; Boyer, L.A. Polycomb group proteins set the stage for early lineage commitment. Cell Stem Cell 2010, 7, 288–298. [Google Scholar] [CrossRef] [Green Version]
  123. Wang, H.; Wang, L.; Erdjument-Bromage, H.; Vidal, M.; Tempst, P.; Jones, R.S.; Zhang, Y. Role of histone H2A ubiquitination in Polycomb silencing. Nature 2004, 431, 873–878. [Google Scholar] [CrossRef] [PubMed]
  124. Yang, Y.; Li, G. Post-translational modifications of PRC2: Signals directing its activity. Epigenet. Chromatin 2020, 13, 47. [Google Scholar] [CrossRef] [PubMed]
  125. Glancy, E.; Ciferri, C.; Bracken, A.P. Structural basis for PRC2 engagement with chromatin. Curr. Opin. Struct. Biol. 2021, 67, 135–144. [Google Scholar] [CrossRef] [PubMed]
  126. Kouznetsova, V.L.; Tchekanov, A.; Li, X.; Yan, X.; Tsigelny, I.F. Polycomb repressive 2 complex-Molecular mechanisms of function. Protein Sci. 2019, 28, 1387–1399. [Google Scholar] [CrossRef] [PubMed]
  127. Bieluszewski, T.; Xiao, J.; Yang, Y.; Wagner, D. PRC2 activity, recruitment, and silencing: A comparative perspective. Trends Plant Sci. 2021, 26, 1186–1198. [Google Scholar] [CrossRef] [PubMed]
  128. Martin, C.J.; Moorehead, R.A. Polycomb repressor complex 2 function in breast cancer (Review). Int. J. Oncol. 2020, 57, 1085–1094. [Google Scholar] [CrossRef]
  129. Kasinath, V.; Beck, C.; Sauer, P.; Poepsel, S.; Kosmatka, J.; Faini, M.; Toso, D.; Aebersold, R.; Nogales, E. JARID2 and AEBP2 regulate PRC2 in the presence of H2AK119ub1 and other histone modifications. Science 2021, 371. [Google Scholar] [CrossRef]
  130. Allas, L.; Brochard, S.; Rochoux, Q.; Ribet, J.; Dujarrier, C.; Veyssiere, A.; Aury-Landas, J.; Grard, O.; Leclercq, S.; Vivien, D.; et al. EZH2 inhibition reduces cartilage loss and functional impairment related to osteoarthritis. Sci. Rep. 2020, 10, 19577. [Google Scholar] [CrossRef]
  131. Grandi, F.C.; Bhutani, N. Epigenetic Therapies for Osteoarthritis. Trends Pharmacol. Sci. 2020, 41, 557–569. [Google Scholar] [CrossRef]
  132. Culley, K.L.; Dragomir, C.L.; Chang, J.; Wondimu, E.B.; Coico, J.; Plumb, D.A.; Otero, M.; Goldring, M.B. Mouse models of osteoarthritis: Surgical model of posttraumatic osteoarthritis induced by destabilization of the medial meniscus. Methods Mol. Biol. 2015, 1226, 143–173. [Google Scholar] [CrossRef]
  133. Glasson, S.S.; Blanchet, T.J.; Morris, E.A. The surgical destabilization of the medial meniscus (DMM) model of osteoarthritis in the 129/SvEv mouse. Osteoarthr. Cartil. 2007, 15, 1061–1069. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  134. Chen, L.; Wu, Y.; Wu, Y.; Wang, Y.; Sun, L.; Li, F. The inhibition of EZH2 ameliorates osteoarthritis development through the Wnt/β-catenin pathway. Sci. Rep. 2016, 6, 29176. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  135. Du, X.; Chen, Y.; Zhang, Q.; Lin, J.; Yu, Y.; Pan, Z.; Sun, H.; Yuan, C.; Yu, D.; Wu, H. Ezh2 Ameliorates Osteoarthritis by Activating TNFSF13B. J. Bone Miner. Res. 2020, 35, 956–965. [Google Scholar] [CrossRef] [PubMed]
  136. Dudakovic, A.; Camilleri, E.T.; Xu, F.; Riester, S.M.; McGee-Lawrence, M.E.; Bradley, E.W.; Paradise, C.R.; Lewallen, E.A.; Thaler, R.; Deyle, D.R.; et al. Epigenetic Control of Skeletal Development by the Histone Methyltransferase Ezh2. J. Biol. Chem. 2015, 290, 27604–27617. [Google Scholar] [CrossRef] [Green Version]
  137. Liu, N.; Zhu, B. Chapter 10—Regulation of PRC2 Activity. In Polycomb Group Proteins; Pirrotta, V., Ed.; Academic Press: Cambridge, MA, USA, 2017; pp. 225–258. [Google Scholar]
  138. Schmitges, F.W.; Prusty, A.B.; Faty, M.; Stützer, A.; Lingaraju, G.M.; Aiwazian, J.; Sack, R.; Hess, D.; Li, L.; Zhou, S.; et al. Histone Methylation by PRC2 Is Inhibited by Active Chromatin Marks. Mol. Cell 2011, 42, 330–341. [Google Scholar] [CrossRef] [Green Version]
  139. Schipani, E.; Ryan, H.E.; Didrickson, S.; Kobayashi, T.; Knight, M.; Johnson, R.S. Hypoxia in cartilage: HIF-1alpha is essential for chondrocyte growth arrest and survival. Genes Dev. 2001, 15, 2865–2876. [Google Scholar] [CrossRef]
  140. Mirzamohammadi, F.; Papaioannou, G.; Inloes, J.; Rankin, E.; Xie, H.; Schipani, E.; Orkin, S.; Kobayashi, T. Polycomb repressive complex 2 regulates skeletal growth by suppressing Wnt and TGF-β signalling. Nat. Commun. 2016, 7, 12047. [Google Scholar] [CrossRef]
  141. Lunter, G.; Ponting, C.P.; Hein, J. Genome-Wide Identification of Human Functional DNA Using a Neutral Indel Model. PLoS Comput. Biol. 2006, 2, e5. [Google Scholar] [CrossRef] [Green Version]
  142. Mattick, J.S.; Makunin, I.V. Non-coding RNA. Hum. Mol. Genet. 2006, 15, R17–R29. [Google Scholar] [CrossRef] [Green Version]
  143. Brockdorff, N.; Ashworth, A.; Kay, G.F.; McCabe, V.M.; Norris, D.P.; Cooper, P.J.; Swift, S.; Rastan, S. The product of the mouse Xist gene is a 15 kb inactive X-specific transcript containing no conserved ORF and located in the nucleus. Cell 1992, 71, 515–526. [Google Scholar] [CrossRef]
  144. Chaumeil, J.; Le Baccon, P.; Wutz, A.; Heard, E. A novel role for Xist RNA in the formation of a repressive nuclear compartment into which genes are recruited when silenced. Gene Dev. 2006, 20, 2223–2237. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  145. Rinn, J.; Guttman, M. RNA and dynamic nuclear organization. Science 2014, 345, 1240–1241. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  146. Bayne, E.H.; Allshire, R.C. RNA-directed transcriptional gene silencing in mammals. Trends Genet. 2005, 21, 370–373. [Google Scholar] [CrossRef] [PubMed]
  147. Corey, D.R. Regulating mammalian transcription with RNA. Trends Biochem. Sci. 2005, 30, 655–658. [Google Scholar] [CrossRef]
  148. Sondag, G.R.; Haqqi, T.M. The Role of MicroRNAs and Their Targets in Osteoarthritis. Curr. Rheumatol. Rep. 2016, 18, 56. [Google Scholar] [CrossRef]
  149. Jiang, S.-D.; Lu, J.; Deng, Z.-H.; Li, Y.-S.; Lei, G.-H. Long noncoding RNAs in osteoarthritis. Jt. Bone Spine 2017, 84, 553–556. [Google Scholar] [CrossRef]
  150. Mao, X.; Cao, Y.; Guo, Z.; Wang, L.; Xiang, C. Biological roles and therapeutic potential of circular RNAs in osteoarthritis. Mol. Ther. Nucleic Acids 2021, 24, 856–867. [Google Scholar] [CrossRef]
  151. Lam, J.K.W.; Chow, M.Y.T.; Zhang, Y.; Leung, S.W.S. siRNA Versus miRNA as Therapeutics for Gene Silencing. Mol. Ther. Nucleic Acids 2015, 4, e252. [Google Scholar] [CrossRef] [Green Version]
  152. Carthew, R.W.; Sontheimer, E.J. Origins and Mechanisms of miRNAs and siRNAs. Cell 2009, 136, 642–655. [Google Scholar] [CrossRef] [Green Version]
  153. Baulcombe, D. RNA silencing. Trends Biochem Sci 2005, 30, 290–293. [Google Scholar] [CrossRef]
  154. Akagi, R.; Sasho, T.; Saito, M.; Endo, J.; Yamaguchi, S.; Muramatsu, Y.; Mukoyama, S.; Akatsu, Y.; Katsuragi, J.; Fukawa, T. Effective knock down of matrix metalloproteinase-13 by an intra-articular injection of small interfering RNA (siRNA) in a murine surgically-induced osteoarthritis model. J. Orthop. Res. 2014, 32, 1175–1180. [Google Scholar] [CrossRef] [PubMed]
  155. Nakagawa, R.; Akagi, R.; Yamaguchi, S.; Enomoto, T.; Sato, Y.; Kimura, S.; Ogawa, Y.; Sadamasu, A.; Ohtori, S.; Sasho, T. Single vs. repeated matrix metalloproteinase-13 knockdown with intra-articular short interfering RNA administration in a murine osteoarthritis model. Connect. Tissue Res. 2019, 60, 335–343. [Google Scholar] [CrossRef] [PubMed]
  156. Bedingfield, S.K.; Colazo, J.M.; Yu, F.; Liu, D.D.; Jackson, M.A.; Himmel, L.E.; Cho, H.; Crofford, L.J.; Hasty, K.A.; Duvall, C.L. Amelioration of post-traumatic osteoarthritis via nanoparticle depots delivering small interfering RNA to damaged cartilage. Nat. Biomed. Eng. 2021, 5, 1069–1083. [Google Scholar] [CrossRef] [PubMed]
  157. Schiffelers, R.M.; Xu, J.; Storm, G.; Woodle, M.C.; Scaria, P.V. Effects of treatment with small interfering RNA on joint inflammation in mice with collagen-induced arthritis. Arthritis Rheum. 2005, 52, 1314–1318. [Google Scholar] [CrossRef] [Green Version]
  158. Rai, M.F.; Pan, H.; Yan, H.; Sandell, L.J.; Pham, C.T.N.; Wickline, S.A. Applications of RNA interference in the treatment of arthritis. Transl. Res. 2019, 214, 1–16. [Google Scholar] [CrossRef]
  159. Tang, X.; Muhammad, H.; McLean, C.; Miotla-Zarebska, J.; Fleming, J.; Didangelos, A.; Onnerfjord, P.; Leask, A.; Saklatvala, J.; Vincent, T.L. Connective tissue growth factor contributes to joint homeostasis and osteoarthritis severity by controlling the matrix sequestration and activation of latent TGFbeta. Ann. Rheum. Dis. 2018, 77, 1372–1380. [Google Scholar] [CrossRef] [Green Version]
  160. Yan, H.; Duan, X.; Pan, H.; Holguin, N.; Rai, M.F.; Akk, A.; Springer, L.E.; Wickline, S.A.; Sandell, L.J.; Pham, C.T.N. Suppression of NF-κB activity via nanoparticle-based siRNA delivery alters early cartilage responses to injury. Proc. Natl. Acad. Sci. USA 2016, 113, E6199–E6208. [Google Scholar] [CrossRef] [Green Version]
  161. Felekkis, K.; Touvana, E.; Stefanou, C.; Deltas, C. microRNAs: A newly described class of encoded molecules that play a role in health and disease. Hippokratia 2010, 14, 236–240. [Google Scholar]
  162. Bartel, D.P. MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell 2004, 116, 281–297. [Google Scholar] [CrossRef] [Green Version]
  163. He, L.; Hannon, G.J. MicroRNAs: Small RNAs with a big role in gene regulation. Nat. Rev. Genet. 2004, 5, 522–531. [Google Scholar] [CrossRef]
  164. Li, L.; Jia, J.; Liu, X.; Yang, S.; Ye, S.; Yang, W.; Zhang, Y. MicroRNA-16-5p controls development of osteoarthritis by targeting SMAD3 in chondrocytes. Curr. Pharm. Des. 2015, 21, 5160–5167. [Google Scholar] [CrossRef] [PubMed]
  165. O’Brien, J.; Hayder, H.; Zayed, Y.; Peng, C. Overview of microRNA biogenesis, mechanisms of actions, and circulation. Front. Endocrinol. 2018, 9, 402. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  166. Song, J.; Kim, D.; Chun, C.-H.; Jin, E.-J. MicroRNA-9 regulates survival of chondroblasts and cartilage integrity by targeting protogenin. Cell Commun. Signal. 2013, 11, 66. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  167. Treiber, T.; Treiber, N.; Meister, G. Regulation of microRNA biogenesis and its crosstalk with other cellular pathways. Nat. Rev. Mol. Cell Biol. 2019, 20, 5–20. [Google Scholar] [CrossRef]
  168. Jones, S.; Watkins, G.; Le Good, N.; Roberts, S.; Murphy, C.; Brockbank, S.; Needham, M.; Read, S.; Newham, P. The identification of differentially expressed microRNA in osteoarthritic tissue that modulate the production of TNF-α and MMP13. Osteoarthr. Cartil. 2009, 17, 464–472. [Google Scholar] [CrossRef] [Green Version]
  169. Makki, M.S.; Haseeb, A.; Haqqi, T.M. MicroRNA-9 promotes IL-6 expression by inhibiting MCPIP1 expression in IL-1β-stimulated human chondrocytes. Arthritis Rheumatol. 2015, 67, 2117. [Google Scholar] [CrossRef]
  170. Araldi, E.; Schipani, E. MicroRNA-140 and the silencing of osteoarthritis. Genes Dev. 2010, 24, 1075–1080. [Google Scholar] [CrossRef] [Green Version]
  171. Min, Z. MicroRNAs associated with osteoarthritis differently expressed in bone matrix gelatin (BMG) rat model. Int. J. Clin. Exp. Med. 2015, 8, 1009. [Google Scholar]
  172. Miyaki, S.; Sato, T.; Inoue, A.; Otsuki, S.; Ito, Y.; Yokoyama, S.; Kato, Y.; Takemoto, F.; Nakasa, T.; Yamashita, S. MicroRNA-140 plays dual roles in both cartilage development and homeostasis. Genes Dev. 2010, 24, 1173–1185. [Google Scholar] [CrossRef] [Green Version]
  173. Miyaki, S.; Nakasa, T.; Otsuki, S.; Grogan, S.P.; Higashiyama, R.; Inoue, A.; Kato, Y.; Sato, T.; Lotz, M.K.; Asahara, H. MicroRNA-140 is expressed in differentiated human articular chondrocytes and modulates interleukin-1 responses. Arthritis Rheum. 2009, 60, 2723–2730. [Google Scholar] [CrossRef] [Green Version]
  174. Nugent, M. MicroRNAs: Exploring new horizons in osteoarthritis. Osteoarthr. Cartil. 2016, 24, 573–580. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  175. Vonk, L.A.; Kragten, A.H.; Dhert, W.; Saris, D.B.; Creemers, L.B. Overexpression of hsa-miR-148a promotes cartilage production and inhibits cartilage degradation by osteoarthritic chondrocytes. Osteoarthr. Cartil. 2014, 22, 145–153. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  176. Liu, J.; Yu, Q.; Ye, Y.; Yan, Y.; Chen, X. Abnormal expression of miR-4784 in chondrocytes of osteoarthritis and associations with chondrocyte hyperplasia. Exp. Ther. Med. 2018, 16, 4690–4694. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  177. Xie, F.; Liu, Y.L.; Chen, X.Y.; Li, Q.; Zhong, J.; Dai, B.Y.; Shao, X.F.; Wu, G.B. Role of MicroRNA, LncRNA, and exosomes in the progression of osteoarthritis: A review of recent literature. Orthop. Surg. 2020, 12, 708–716. [Google Scholar] [CrossRef]
  178. Wang, J.; Chen, L.; Jin, S.; Lin, J.; Zheng, H.; Zhang, H.; Fan, H.; He, F.; Ma, S.; Li, Q. Altered expression of microRNA-98 in IL-1β-induced cartilage degradation and its role in chondrocyte apoptosis Corrigendum in/10.3892/mmr. 2018.8794. Mol. Med. Rep. 2017, 16, 3208–3216. [Google Scholar] [CrossRef] [Green Version]
  179. Zhai, X.; Meng, R.; Li, H.; Li, J.; Jing, L.; Qin, L.; Gao, Y. miR-181a modulates chondrocyte apoptosis by targeting glycerol-3-phosphate dehydrogenase 1-like protein (GPD1L) in osteoarthritis. Med. Sci. Monit. 2017, 23, 1224. [Google Scholar] [CrossRef] [Green Version]
  180. Dai, L.; Zhang, X.; Hu, X.; Zhou, C.; Ao, Y. Silencing of microRNA-101 prevents IL-1β-induced extracellular matrix degradation in chondrocytes. Arthritis Res. Ther. 2012, 14, R268. [Google Scholar] [CrossRef] [Green Version]
  181. Kung, L.H.; Ravi, V.; Rowley, L.; Bell, K.M.; Little, C.B.; Bateman, J.F. Comprehensive expression analysis of microRNAs and mRNAs in synovial tissue from a mouse model of early post-traumatic osteoarthritis. Sci. Rep. 2017, 7, 17701. [Google Scholar]
  182. Cheleschi, S.; Gallo, I.; Barbarino, M.; Giannotti, S.; Mondanelli, N.; Giordano, A.; Tenti, S.; Fioravanti, A. MicroRNA mediate visfatin and resistin induction of oxidative stress in human osteoarthritic synovial fibroblasts via NF-κB pathway. Int. J. Mol. Sci. 2019, 20, 5200. [Google Scholar] [CrossRef] [Green Version]
  183. Tavallaee, G.; Rockel, J.S.; Lively, S.; Kapoor, M. MicroRNAs in synovial pathology associated with osteoarthritis. Front. Med. 2020, 7, 376. [Google Scholar] [CrossRef]
  184. Wade, S.M.; Ohnesorge, N.; McLoughlin, H.; Biniecka, M.; Carter, S.P.; Trenkman, M.; Cunningham, C.C.; McGarry, T.; Canavan, M.; Kennedy, B.N. Dysregulated miR-125a promotes angiogenesis through enhanced glycolysis. EBioMedicine 2019, 47, 402–413. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  185. Xia, S.; Yan, K.; Wang, Y. Increased miR-381a-3p contributes to osteoarthritis by targeting IkBα. Ann. Clin. Lab. Sci. 2016, 46, 247–253. [Google Scholar] [PubMed]
  186. Yang, C.-R.; Shih, K.-S.; Liou, J.-P.; Wu, Y.-W.; Hsieh, I.-N.; Lee, H.-Y.; Lin, T.-C.; Wang, J.-H. Denbinobin upregulates miR-146a expression and attenuates IL-1β-induced upregulation of ICAM-1 and VCAM-1 expressions in osteoarthritis fibroblast-like synoviocytes. J. Mol. Med. 2014, 92, 1147–1158. [Google Scholar] [CrossRef] [PubMed]
  187. Jin, Z.; Ren, J.; Qi, S. Human bone mesenchymal stem cells-derived exosomes overexpressing microRNA-26a-5p alleviate osteoarthritis via down-regulation of PTGS2. Int. Immunopharmacol. 2020, 78, 105946. [Google Scholar] [CrossRef]
  188. Wang, J.; Shih, K.; Wu, Y.; Wang, A.; Yang, C. Histone deacetylase inhibitors increase microRNA-146a expression and enhance negative regulation of interleukin-1β signaling in osteoarthritis fibroblast-like synoviocytes. Osteoarthr. Cartil. 2013, 21, 1987–1996. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  189. Wang, Q.; Wang, W.; Zhang, F.; Deng, Y.; Long, Z. NEAT1/miR-181c regulates osteopontin (OPN)-mediated synoviocyte proliferation in osteoarthritis. J. Cell. Biochem. 2017, 118, 3775–3784. [Google Scholar] [CrossRef]
  190. Ma, L.; Bajic, V.B.; Zhang, Z. On the classification of long non-coding RNAs. RNA Biol. 2013, 10, 924–933. [Google Scholar] [CrossRef]
  191. Li, C.H.; Chen, Y. Targeting long non-coding RNAs in cancers: Progress and prospects. Int. J. Biochem. Cell Biol. 2013, 45, 1895–1910. [Google Scholar] [CrossRef]
  192. Gibb, E.A.; Brown, C.J.; Lam, W.L. The functional role of long non-coding RNA in human carcinomas. Mol. Cancer 2011, 10, 38. [Google Scholar] [CrossRef] [Green Version]
  193. Marques-Rocha, J.L.; Samblas, M.; Milagro, F.I.; Bressan, J.; Martínez, J.A.; Marti, A. Noncoding RNAs, cytokines, and inflammation-related diseases. FASEB J. 2015, 29, 3595–3611. [Google Scholar] [CrossRef] [Green Version]
  194. Bao, Z.; Yang, Z.; Huang, Z.; Zhou, Y.; Cui, Q.; Dong, D. LncRNADisease 2.0: An updated database of long non-coding RNA-associated diseases. Nucleic Acids Res. 2019, 47, D1034–D1037. [Google Scholar] [CrossRef] [PubMed]
  195. Fernandes, J.C.; Acuña, S.M.; Aoki, J.I.; Floeter-Winter, L.M.; Muxel, S.M. Long non-coding RNAs in the regulation of gene expression: Physiology and disease. Non-Coding RNA 2019, 5, 17. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  196. Aigner, T.; Söder, S.; Gebhard, P.M.; McAlinden, A.; Haag, J. Mechanisms of disease: Role of chondrocytes in the pathogenesis of osteoarthritis—structure, chaos and senescence. Nat. Clin. Pract. Rheumatol. 2007, 3, 391–399. [Google Scholar] [CrossRef] [PubMed]
  197. Wang, J.; Sun, Y.; Liu, J.; Yang, B.; Wang, T.; Zhang, Z.; Jiang, X.; Guo, Y.; Zhang, Y. Roles of long non-coding RNA in osteoarthritis. Int. J. Mol. Med. 2021, 48, 133. [Google Scholar] [CrossRef]
  198. Xing, D.; Liang, J.-Q.; Li, Y.; Lu, J.; Jia, H.-B.; Xu, L.-Y.; Ma, X.-L. Identification of Long Noncoding RNA Associated with Osteoarthritis in Humans. Orthop. Surg. 2014, 6, 288–293. [Google Scholar] [CrossRef]
  199. Song, J.; Ahn, C.; Chun, C.H.; Jin, E.J. A long non-coding RNA, GAS5, plays a critical role in the regulation of miR-21 during osteoarthritis. J. Orthop. Res. 2014, 32, 1628–1635. [Google Scholar] [CrossRef]
  200. Zhang, C.; Wang, P.; Jiang, P.; Lv, Y.; Dong, C.; Dai, X.; Tan, L.; Wang, Z. Upregulation of lncRNA HOTAIR contributes to IL-1β-induced MMP overexpression and chondrocytes apoptosis in temporomandibular joint osteoarthritis. Gene 2016, 586, 248–253. [Google Scholar] [CrossRef] [Green Version]
  201. Nanus, D.E.; Wijesinghe, S.N.; Pearson, M.J.; Hadjicharalambous, M.R.; Rosser, A.; Davis, E.T.; Lindsay, M.; Jones, S.W. Obese osteoarthritis patients exhibit an inflammatory synovial fibroblast phenotype, which is regulated by the long non coding RNA MALAT1. Arthritis Rheumatol. 2019, 72, 1–29. [Google Scholar]
  202. Zhang, Y.; Wang, F.; Chen, G.; He, R.; Yang, L. LncRNA MALAT1 promotes osteoarthritis by modulating miR-150-5p/AKT3 axis. Cell Biosci. 2019, 9, 54. [Google Scholar] [CrossRef]
  203. Gómez, R.; Villalvilla, A.; Largo, R.; Gualillo, O.; Herrero-Beaumont, G. TLR4 signalling in osteoarthritis—Finding targets for candidate DMOADs. Nat. Rev. Rheumatol. 2015, 11, 159–170. [Google Scholar] [CrossRef]
  204. Fu, M.; Huang, G.; Zhang, Z.; Liu, J.; Zhang, Z.; Huang, Z.; Yu, B.; Meng, F. Expression profile of long noncoding RNAs in cartilage from knee osteoarthritis patients. Osteoarthr. Cartil. 2015, 23, 423–432. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  205. Jeck, W.R.; Sharpless, N.E. Detecting and characterizing circular RNAs. Nat. Biotechnol. 2014, 32, 453–461. [Google Scholar] [CrossRef] [PubMed]
  206. Jeck, W.R.; Sorrentino, J.A.; Wang, K.; Slevin, M.K.; Burd, C.E.; Liu, J.; Marzluff, W.F.; Sharpless, N.E. Circular RNAs are abundant, conserved, and associated with ALU repeats. RNA 2013, 19, 141–157. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  207. Abe, N.; Matsumoto, K.; Nishihara, M.; Nakano, Y.; Shibata, A.; Maruyama, H.; Shuto, S.; Matsuda, A.; Yoshida, M.; Ito, Y.; et al. Rolling Circle Translation of Circular RNA in Living Human Cells. Sci. Rep. 2015, 5, 16435. [Google Scholar] [CrossRef] [PubMed]
  208. Liu, D.; Liang, Y.-H.; Yang, Y.-T.; He, M.; Cai, Z.-J.; Xiao, W.-F.; Li, Y.-S. Circular RNA in osteoarthritis: An updated insight into the pathophysiology and therapeutics. Am. J. Transl. Res. 2021, 13, 11–23. [Google Scholar]
  209. Ni, J.; Dang, X.; Shi, Z. CircPSM3 inhibits the proliferation and differentiation of OA chondrocytes by targeting miRNA-296-5p. Eur. Rev. Med. Pharmacol. Sci. 2020, 24, 3467–3475. [Google Scholar]
  210. Sui, C.; Liu, D.; Que, Y.; Xu, S.; Hu, Y. Knockdown of hsa_circ_0037658 inhibits the progression of osteoarthritis via inducing autophagy. Hum. Cell 2021, 34, 76–85. [Google Scholar] [CrossRef]
  211. Zhu, H.; Hu, Y.; Wang, C.; Zhang, X.; He, D. CircGCN1L1 promotes synoviocyte proliferation and chondrocyte apoptosis by targeting miR-330-3p and TNF-α in TMJ osteoarthritis. Cell Death Dis. 2020, 11, 284. [Google Scholar] [CrossRef]
  212. Shen, S.; Wu, Y.; Chen, J.; Xie, Z.; Huang, K.; Wang, G.; Yang, Y.; Ni, W.; Chen, Z.; Shi, P.; et al. CircSERPINE2 protects against osteoarthritis by targeting miR-1271 and ETS-related gene. Ann. Rheum. Dis. 2019, 78, 826–836. [Google Scholar] [CrossRef] [Green Version]
  213. Shen, P.; Yang, Y.; Liu, G.; Chen, W.; Chen, J.; Wang, Q.; Gao, H.; Fan, S.; Shen, S.; Zhao, X. CircCDK14 protects against osteoarthritis by sponging miR-125a-5p and promoting the expression of Smad2. Theranostics 2020, 10, 9113. [Google Scholar] [CrossRef]
  214. Li, H.-Z.; Lin, Z.; Xu, X.-H.; Lin, N.; Lu, H.-D. The potential roles of circRNAs in osteoarthritis: A coming journey to find a treasure. Biosci. Rep. 2018, 38. [Google Scholar] [CrossRef] [PubMed]
  215. Su, Q.; Lv, X. Revealing new landscape of cardiovascular disease through circular RNA-miRNA-mRNA axis. Genomics 2020, 112, 1680–1685. [Google Scholar] [CrossRef] [PubMed]
  216. Ng, M.; Fleming, T.; Robinson, M.; Thomson, B.; Graetz, N.; Margono, C.; Mullany, E.C.; Biryukov, S.; Abbafati, C.; Abera, S.F. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: A systematic analysis for the Global Burden of Disease Study 2013. Lancet 2014, 384, 766–781. [Google Scholar] [CrossRef] [Green Version]
  217. Anderson, J.J.; Felson, D.T. Factors associated with osteoarthritis of the knee in the first national Health and Nutrition Examination Survey (HANES I) evidence for an association with overweight, race, and physical demands of work. Am. J. Epidemiol. 1988, 128, 179–189. [Google Scholar] [CrossRef] [PubMed]
  218. Ayral, X.; Pickering, E.; Woodworth, T.; Mackillop, N.; Dougados, M. Synovitis: A potential predictive factor of structural progression of medial tibiofemoral knee osteoarthritis–results of a 1 year longitudinal arthroscopic study in 422 patients. Osteoarthr. Cartil. 2005, 13, 361–367. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  219. Jin, X.; Gibson, A.A.; Gale, J.; Schneuer, F.; Ding, D.; March, L.; Sainsbury, A.; Nassar, N. Does weight loss reduce the incidence of total knee and hip replacement for osteoarthritis?—A prospective cohort study among middle-aged and older adults with overweight or obesity. Int. J. Obes. 2021, 45, 1696–1704. [Google Scholar] [CrossRef] [PubMed]
  220. Panunzi, S.; Maltese, S.; De Gaetano, A.; Capristo, E.; Bornstein, S.R.; Mingrone, G. Comparative efficacy of different weight loss treatments on knee osteoarthritis: A network meta-analysis. Obes. Rev. 2021, 22, e13230. [Google Scholar] [CrossRef]
  221. Webb, E.J.; Osmotherly, P.G.; Baines, S.K. Physical function after dietary weight loss in overweight and obese adults with osteoarthritis: A systematic review and meta-analysis. Public Health Nutr. 2021, 24, 338–353. [Google Scholar] [CrossRef]
  222. Conway, R.; McCarthy, G.M. Obesity and osteoarthritis: More than just mechanics. EMJ Rheumatol. 2015, 2, 75–83. [Google Scholar]
  223. Goldstein, B.J.; Scalia, R. Adiponectin: A novel adipokine linking adipocytes and vascular function. J. Clin. Endocrinol. Metab. 2004, 89, 2563–2568. [Google Scholar] [CrossRef] [Green Version]
  224. Kwon, H.; Pessin, J.E. Adipokines mediate inflammation and insulin resistance. Front. Endocrinol. 2013, 4, 71. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  225. Lo, J.C.; Ljubicic, S.; Leibiger, B.; Kern, M.; Leibiger, I.B.; Moede, T.; Kelly, M.E.; Bhowmick, D.C.; Murano, I.; Cohen, P. Adipsin is an adipokine that improves β cell function in diabetes. Cell 2014, 158, 41–53. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  226. Stein, S.; Bachmann, A.; Lossner, U.; Kratzsch, J.R.; BLuher, M.; Stumvoll, M.; Fasshauer, M. Serum levels of the adipokine FGF21 depend on renal function. Diabetes Care 2009, 32, 126–128. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  227. Swisher, A.K.; Abraham, J.; Bonner, D.; Gilleland, D.; Hobbs, G.; Kurian, S.; Yanosik, M.A.; Vona-Davis, L. Exercise and dietary advice intervention for survivors of triple-negative breast cancer: Effects on body fat, physical function, quality of life, and adipokine profile. Support. Care Cancer 2015, 23, 2995–3003. [Google Scholar] [CrossRef] [Green Version]
  228. Conde, J.; Scotece, M.; López, V.; Abella, V.; Hermida, M.; Pino, J.; Lago, F.; Gómez-Reino, J.J.; Gualillo, O. Differential expression of adipokines in infrapatellar fat pad (IPFP) and synovium of osteoarthritis patients and healthy individuals. Ann. Rheum. Dis. 2014, 73, 631–633. [Google Scholar] [CrossRef]
  229. Fowler-Brown, A.; Kim, D.H.; Shi, L.; Marcantonio, E.; Wee, C.C.; Shmerling, R.H.; Leveille, S. The mediating effect of leptin on the relationship between body weight and knee osteoarthritis in older adults. Arthritis Rheumatol. 2015, 67, 169–175. [Google Scholar] [CrossRef]
  230. Honsawek, S.; Chayanupatkul, M. Correlation of plasma and synovial fluid adiponectin with knee osteoarthritis severity. Arch. Med. Res. 2010, 41, 593–598. [Google Scholar] [CrossRef]
  231. Lübbert, M.; Suciu, S.; Baila, L.; Rüter, B.H.; Platzbecker, U.; Giagounidis, A.; Selleslag, D.; Labar, B.; Germing, U.; Salih, H.R. Low-dose decitabine versus best supportive care in elderly patients with intermediate-or high-risk myelodysplastic syndrome (MDS) ineligible for intensive chemotherapy: Final results of the randomized phase III study of the European Organisation for Research and Treatment of Cancer Leukemia Group and the German MDS Study Group. J. Clin. Oncol. 2011, 29, 1987–1996. [Google Scholar]
  232. Tilg, H.; Moschen, A.R. Adipocytokines: Mediators linking adipose tissue, inflammation and immunity. Nat. Rev. Immunol. 2006, 6, 772–783. [Google Scholar] [CrossRef]
  233. Yang, S.; Ryu, J.-H.; Oh, H.; Jeon, J.; Kwak, J.-S.; Kim, J.-H.; Kim, H.A.; Chun, C.-H.; Chun, J.-S. NAMPT (visfatin), a direct target of hypoxia-inducible factor-2α, is an essential catabolic regulator of osteoarthritis. Ann. Rheum. Dis. 2015, 74, 595–602. [Google Scholar] [CrossRef] [Green Version]
  234. Zhang, Z.; Xing, X.; Hensley, G.; Chang, L.W.; Liao, W.; Abu-Amer, Y.; Sandell, L.J. Resistin induces expression of proinflammatory cytokines and chemokines in human articular chondrocytes via transcription and messenger RNA stabilization. Arthritis Rheum. 2010, 62, 1993–2003. [Google Scholar] [PubMed] [Green Version]
  235. Milagro, F.I.; Miranda, J.; Portillo, M.P.; Fernandez-Quintela, A.; Campion, J.; Martínez, J.A. High-throughput sequencing of microRNAs in peripheral blood mononuclear cells: Identification of potential weight loss biomarkers. PLoS ONE 2013, 8, e54319. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  236. Ortega, F.J.; Mercader, J.M.; Catalan, V.; Moreno-Navarrete, J.M.; Pueyo, N.; Sabater, M.; Gomez-Ambrosi, J.; Anglada, R.; Fernández-Formoso, J.A.; Ricart, W. Targeting the circulating microRNA signature of obesity. Clin. Chem. 2013, 59, 781–792. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  237. Maegdefessel, L. The emerging role of micro RNA s in cardiovascular disease. J. Intern. Med. 2014, 276, 633–644. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  238. Fujisawa, T.; Hattori, T.; Takahashi, K.; Kuboki, T.; Yamashita, A.; Takigawa, M. Cyclic mechanical stress induces extracellular matrix degradation in cultured chondrocytes via gene expression of matrix metalloproteinases and interleukin-1. J. Biochem. 1999, 125, 966–975. [Google Scholar] [CrossRef] [PubMed]
  239. Capparelli, R.; Iannelli, D. Role of epigenetics in type 2 diabetes and obesity. Biomedicines 2021, 9, 977. [Google Scholar] [CrossRef] [PubMed]
  240. Gao, W.; Liu, J.-L.; Lu, X.; Yang, Q. Epigenetic regulation of energy metabolism in obesity. J. Mol. Cell Biol. 2021, 13, 480–499. [Google Scholar] [CrossRef]
  241. Masi, S.; Ambrosini, S.; Mohammed, S.A.; Sciarretta, S.; Lüscher, T.F.; Paneni, F.; Costantino, S. Epigenetic remodeling in obesity-related vascular disease. Antioxid. Redox Signal. 2021, 34, 1165–1199. [Google Scholar] [CrossRef]
  242. Cheong, Y.; Nishitani, S.; Yu, J.; Habata, K.; Kamiya, T.; Shiotsu, D.; Omori, I.M.; Okazawa, H.; Tomoda, A.; Kosaka, H. The effects of epigenetic age and its acceleration on surface area, cortical thickness, and volume in young adults. Cereb. Cortex 2022, bhac043. [Google Scholar] [CrossRef]
  243. Galow, A.-M.; Peleg, S. How to Slow down the Ticking Clock: Age-Associated Epigenetic Alterations and Related Interventions to Extend Life Span. Cells 2022, 11, 468. [Google Scholar] [CrossRef]
  244. Zabransky, D.J.; Jaffee, E.M.; Weeraratna, A.T. Shared genetic and epigenetic changes link aging and cancer. Trends Cell Biol. 2022, 32, 338–350. [Google Scholar] [CrossRef] [PubMed]
  245. Ramos, Y.F.; den Hollander, W.; Bovee, J.V.; Bomer, N.; van der Breggen, R.; Lakenberg, N.; Keurentjes, J.C.; Goeman, J.J.; Slagboom, P.E.; Nelissen, R.G.; et al. Genes involved in the osteoarthritis process identified through genome wide expression analysis in articular cartilage; the RAAK study. PLoS ONE 2014, 9, e103056. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  246. Valdes, A.M.; Spector, T.D. Genetic epidemiology of hip and knee osteoarthritis. Nat. Rev. Rheumatol. 2011, 7, 23–32. [Google Scholar] [CrossRef] [PubMed]
  247. Ecsedi, S.; Rodríguez-Aguilera, J.R.; Hernandez-Vargas, H. 5-Hydroxymethylcytosine (5hmC), or how to identify your favorite cell. Epigenomes 2018, 2, 3. [Google Scholar] [CrossRef] [Green Version]
  248. Taylor, S.E.; Li, Y.H.; Smeriglio, P.; Rath, M.; Wong, W.H.; Bhutani, N. Stable 5-hydroxymethylcytosine (5hmC) acquisition marks gene activation during chondrogenic differentiation. J. Bone Mineral. Res. 2016, 31, 524–534. [Google Scholar] [CrossRef] [Green Version]
  249. Wu, X.; Zhang, Y. TET-mediated active DNA demethylation: Mechanism, function and beyond. Nat. Rev. Genet. 2017, 18, 517–534. [Google Scholar] [CrossRef]
  250. Ratneswaran, A.; Kapoor, M. Osteoarthritis year in review: Genetics, genomics, epigenetics. Osteoarthr. Cartil. 2021, 29, 151–160. [Google Scholar] [CrossRef]
  251. Santiago, M.; Antunes, C.; Guedes, M.; Sousa, N.; Marques, C.J. TET enzymes and DNA hydroxymethylation in neural development and function—How critical are they? Genomics 2014, 104, 334–340. [Google Scholar] [CrossRef] [Green Version]
  252. Smeriglio, P.; Grandi, F.C.; Davala, S.; Masarapu, V.; Indelli, P.F.; Goodman, S.B.; Bhutani, N. Inhibition of TET1 prevents the development of osteoarthritis and reveals the 5hmC landscape that orchestrates pathogenesis. Sci. Transl. Med. 2020, 12, eaax2332. [Google Scholar] [CrossRef]
  253. McHugh, J. TET1: An epigenetic controller of OA. Nat. Rev. Rheumatol. 2020, 16, 351. [Google Scholar] [CrossRef]
  254. Buocikova, V.; Longhin, E.M.; Pilalis, E.; Mastrokalou, C.; Miklikova, S.; Cihova, M.; Poturnayova, A.; Mackova, K.; Babelova, A.; Trnkova, L. Decitabine potentiates efficacy of doxorubicin in a preclinical trastuzumab-resistant HER2-positive breast cancer models. Biomed. Pharmacother. 2022, 147, 112662. [Google Scholar] [CrossRef] [PubMed]
  255. Fang, F.; Zuo, Q.; Pilrose, J.; Wang, Y.; Shen, C.; Li, M.; Wulfridge, P.; Matei, D.; Nephew, K.P. Decitabine reactivated pathways in platinum resistant ovarian cancer. Oncotarget 2014, 5, 3579. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  256. Hagemann, S.; Heil, O.; Lyko, F.; Brueckner, B. Azacytidine and decitabine induce gene-specific and non-random DNA demethylation in human cancer cell lines. PLoS ONE 2011, 6, e17388. [Google Scholar] [CrossRef] [PubMed]
  257. Yu, G.; Wu, Y.; Wang, W.; Xu, J.; Lv, X.; Cao, X.; Wan, T. Low-dose decitabine enhances the effect of PD-1 blockade in colorectal cancer with microsatellite stability by re-modulating the tumor microenvironment. Cell. Mol. Immunol. 2019, 16, 401–409. [Google Scholar] [CrossRef] [PubMed]
  258. Zhao, L.; Wang, Q.; Zhang, C.; Huang, C. Genome-wide DNA methylation analysis of articular chondrocytes identifies TRAF1, CTGF, and CX3CL1 genes as hypomethylated in osteoarthritis. Clin. Rheumatol. 2017, 36, 2335–2342. [Google Scholar] [CrossRef] [PubMed]
  259. Duan, R.; Du, W.; Guo, W. EZH2: A novel target for cancer treatment. J. Hematol. Oncol. 2020, 13, 1–12. [Google Scholar] [CrossRef]
  260. Kim, K.H.; Roberts, C.W. Targeting EZH2 in cancer. Nat. Med. 2016, 22, 128–134. [Google Scholar] [CrossRef]
  261. Stacchiotti, S.; Schoffski, P.; Jones, R.; Agulnik, M.; Villalobos, V.M.; Jahan, T.M.; Chen, T.W.-W.; Italiano, A.; Demetri, G.D.; Cote, G.M. Safety and efficacy of tazemetostat, a first-in-class EZH2 inhibitor, in patients (pts) with epithelioid sarcoma (ES)(NCT02601950). J. Clin. Oncol. 2019, 37, 11003. [Google Scholar] [CrossRef]
  262. Tremblay-LeMay, R.; Rastgoo, N.; Pourabdollah, M.; Chang, H. EZH2 as a therapeutic target for multiple myeloma and other haematological malignancies. Biomark. Res. 2018, 6, 34. [Google Scholar] [CrossRef] [Green Version]
  263. Chen, W.-P.; Bao, J.-P.; Hu, P.-F.; Feng, J.; Wu, L.-D. Alleviation of osteoarthritis by Trichostatin A, a histone deacetylase inhibitor, in experimental osteoarthritis. Mol. Biol. Rep. 2010, 37, 3967–3972. [Google Scholar] [CrossRef]
  264. Qu, H.; Li, J.; Wu, L.D.; Chen, W.P. Trichostatin A increases the TIMP-1/MMP ratio to protect against osteoarthritis in an animal model of the disease. Mol. Med. Rep. 2016, 14, 2423–2430. [Google Scholar] [CrossRef] [Green Version]
  265. Lu, J.; Sun, Y.; Ge, Q.; Teng, H.; Jiang, Q. Histone deacetylase 4 alters cartilage homeostasis in human osteoarthritis. BMC Musculoskelet. Disord. 2014, 15, 438. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  266. Khan, N.M.; Haqqi, T.M. Epigenetics in osteoarthritis: Potential of HDAC inhibitors as therapeutics. Pharmacol. Res. 2018, 128, 73–79. [Google Scholar] [CrossRef]
  267. Bradley, E.W.; Carpio, L.R.; Van Wijnen, A.J.; McGee-Lawrence, M.E.; Westendorf, J.J. Histone deacetylases in bone development and skeletal disorders. Physiol. Rev. 2015, 95, 1359–1381. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  268. Batshon, G.; Elayyan, J.; Qiq, O.; Reich, E.; Ben-Aderet, L.; Kandel, L.; Haze, A.; Steinmeyer, J.; Lefebvre, V.; Zhang, H. Serum NT/CT SIRT1 ratio reflects early osteoarthritis and chondrosenescence. Ann. Rheum. Dis. 2020, 79, 1370–1380. [Google Scholar] [CrossRef] [PubMed]
  269. Matsuzaki, T.; Matsushita, T.; Takayama, K.; Matsumoto, T.; Nishida, K.; Kuroda, R.; Kurosaka, M. Disruption of Sirt1 in chondrocytes causes accelerated progression of osteoarthritis under mechanical stress and during ageing in mice. Ann. Rheum. Dis. 2014, 73, 1397–1404. [Google Scholar] [CrossRef] [PubMed]
  270. Xu, M.; Feng, M.; Peng, H.; Qian, Z.; Zhao, L.; Wu, S. Epigenetic regulation of chondrocyte hypertrophy and apoptosis through Sirt1/P53/P21 pathway in surgery-induced osteoarthritis. Biochem. Biophys. Res. Commun. 2020, 528, 179–185. [Google Scholar] [CrossRef]
  271. Hecht, J.T.; Veerisetty, A.C.; Wu, J.; Coustry, F.; Hossain, M.G.; Chiu, F.; Gannon, F.H.; Posey, K.L. Primary Osteoarthritis Early Joint Degeneration Induced by Endoplasmic Reticulum Stress Is Mitigated by Resveratrol. Am. J. Pathol. 2021, 191, 1624–1637. [Google Scholar] [CrossRef]
  272. Nishida, K.; Matsushita, T.; Takayama, K.; Tanaka, T.; Miyaji, N.; Ibaraki, K.; Araki, D.; Kanzaki, N.; Matsumoto, T.; Kuroda, R. Intraperitoneal injection of the SIRT1 activator SRT1720 attenuates the progression of experimental osteoarthritis in mice. Bone Jt. Res. 2018, 7, 252–262. [Google Scholar] [CrossRef] [Green Version]
  273. Wei, Y.; Jia, J.; Jin, X.; Tong, W.; Tian, H. Resveratrol ameliorates inflammatory damage and protects against osteoarthritis in a rat model of osteoarthritis. Mol. Med. Rep. 2018, 17, 1493–1498. [Google Scholar] [CrossRef]
  274. Cheng, C.; Shan, W.; Huang, W.; Ding, Z.; Cui, G.; Liu, F.; Lu, W.; Xu, J.; He, W.; Yin, Z. ACY-1215 exhibits anti-inflammatory and chondroprotective effects in human osteoarthritis chondrocytes via inhibition of STAT3 and NF-κB signaling pathways. Biomed. Pharmacother. 2019, 109, 2464–2471. [Google Scholar] [CrossRef] [PubMed]
  275. Zhang, H.; Ji, L.; Yang, Y.; Wei, Y.; Zhang, X.; Gang, Y.; Lu, J.; Bai, L. The therapeutic effects of treadmill exercise on osteoarthritis in rats by inhibiting the HDAC3/NF-KappaB pathway in vivo and in vitro. Front. Physiol. 2019, 1060. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  276. Delplace, V.; Boutet, M.A.; Le Visage, C.; Maugars, Y.; Guicheux, J.; Vinatier, C. Osteoarthritis: From upcoming treatments to treatments yet to come. Jt. Bone Spine 2021, 88, 105206. [Google Scholar] [CrossRef] [PubMed]
  277. Safiri, S.; Kolahi, A.A.; Smith, E.; Hill, C.; Bettampadi, D.; Mansournia, M.A.; Hoy, D.; Ashrafi-Asgarabad, A.; Sepidarkish, M.; Almasi-Hashiani, A.; et al. Global, regional and national burden of osteoarthritis 1990–2017: A systematic analysis of the Global Burden of Disease Study 2017. Ann. Rheum. Dis. 2020, 79, 819–828. [Google Scholar] [CrossRef] [PubMed]
  278. Song, Y.; Zhang, J.; Xu, H.; Lin, Z.; Chang, H.; Liu, W.; Kong, L. Mesenchymal stem cells in knee osteoarthritis treatment: A systematic review and meta-analysis. J. Orthop. Translat. 2020, 24, 121–130. [Google Scholar] [CrossRef]
  279. Ankrum, J.A.; Ong, J.F.; Karp, J.M. Mesenchymal stem cells: Immune evasive, not immune privileged. Nat. Biotechnol. 2014, 32, 252–260. [Google Scholar] [CrossRef] [Green Version]
  280. Xing, D.; Liu, W.; Wang, B.; Li, J.J.; Zhao, Y.; Li, H.; Liu, A.; Du, Y.; Lin, J. Intra-articular injection of cell-laden 3D microcryogels empower low-dose cell therapy for osteoarthritis in a rat model. Cell Transplant. 2020, 29, 0963689720932142. [Google Scholar] [CrossRef]
  281. Gong, Y.; Li, S.J.; Liu, R.; Zhan, J.F.; Tan, C.; Fang, Y.F.; Chen, Y.; Yu, B. Inhibition of YAP with siRNA prevents cartilage degradation and ameliorates osteoarthritis development. J. Mol. Med. 2019, 97, 103–114. [Google Scholar] [CrossRef]
  282. Hoshi, H.; Akagi, R.; Yamaguchi, S.; Muramatsu, Y.; Akatsu, Y.; Yamamoto, Y.; Sasaki, T.; Takahashi, K.; Sasho, T. Effect of inhibiting MMP13 and ADAMTS5 by intra-articular injection of small interfering RNA in a surgically induced osteoarthritis model of mice. Cell Tissue Res. 2017, 368, 379–387. [Google Scholar] [CrossRef]
  283. Si, H.B.; Zeng, Y.; Liu, S.Y.; Zhou, Z.K.; Chen, Y.N.; Cheng, J.Q.; Lu, Y.R.; Shen, B. Intra-articular injection of microRNA-140 (miRNA-140) alleviates osteoarthritis (OA) progression by modulating extracellular matrix (ECM) homeostasis in rats. Osteoarthr. Cartil. 2017, 25, 1698–1707. [Google Scholar] [CrossRef] [Green Version]
  284. Ko, J.-Y.; Lee, M.S.; Lian, W.-S.; Weng, W.-T.; Sun, Y.-C.; Chen, Y.-S.; Wang, F.-S. MicroRNA-29a Counteracts Synovitis in Knee Osteoarthritis Pathogenesis by Targeting VEGF. Sci. Rep. 2017, 7, 3584. [Google Scholar] [CrossRef] [PubMed]
  285. Kim, D.; Song, J.; Han, J.; Kim, Y.; Chun, C.-H.; Jin, E.-J. Two non-coding RNAs, MicroRNA-101 and HOTTIP contribute cartilage integrity by epigenetic and homeotic regulation of integrin-α1. Cell. Signal. 2013, 25, 2878–2887. [Google Scholar] [CrossRef] [PubMed]
  286. Liu, Q.; Zhang, X.; Dai, L.; Hu, X.; Zhu, J.; Li, L.; Zhou, C.; Ao, Y. Long Noncoding RNA Related to Cartilage Injury Promotes Chondrocyte Extracellular Matrix Degradation in Osteoarthritis. Arthritis Rheumatol. 2014, 66, 969–978. [Google Scholar] [CrossRef] [PubMed]
  287. Wang, Y.; Wu, C.; Zhang, F.; Zhang, Y.; Ren, Z.; Lammi, M.J.; Guo, X. Screening for Differentially Expressed Circular RNAs in the Cartilage of Osteoarthritis Patients for Their Diagnostic Value. Genet. Test Mol. Biomark. 2019, 23, 706–716. [Google Scholar] [CrossRef] [PubMed]
  288. United Nations; Department of Economic. World Population Ageing, 1950–2050; United Nations Publications: New York, NY, USA, 2002. [Google Scholar]
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Figure 1. Osteoarthritis pathophysiology: Osteoarthritis (OA) is a multifactorial disease affecting cartilage, synovium, the infrapatellar fat pad, and the underlying subchondral bone. OA is characterized by chronic inflammation, cartilage damage due to mechanical and proteolytic degradation and abnormal subchondral bone formation, leading to the formation of bony outgrowths into the joint capsule referred to as osteophytes.
Figure 1. Osteoarthritis pathophysiology: Osteoarthritis (OA) is a multifactorial disease affecting cartilage, synovium, the infrapatellar fat pad, and the underlying subchondral bone. OA is characterized by chronic inflammation, cartilage damage due to mechanical and proteolytic degradation and abnormal subchondral bone formation, leading to the formation of bony outgrowths into the joint capsule referred to as osteophytes.
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Figure 2. Histone modifications in OA: Histone methylation/demethylation and histone acetylation/deacetylation affect genetics architecture and the accessibility of transcriptional activity. The process of histone methylation is governed by histone methyltransferases (HMTs) and histone demethyltransferases (HDMTs). Histone acetylation involves the addition or the removal of an acetyl group by histone acetyltransferases (HATs) or histone deacetylases (HDACs), respectively.
Figure 2. Histone modifications in OA: Histone methylation/demethylation and histone acetylation/deacetylation affect genetics architecture and the accessibility of transcriptional activity. The process of histone methylation is governed by histone methyltransferases (HMTs) and histone demethyltransferases (HDMTs). Histone acetylation involves the addition or the removal of an acetyl group by histone acetyltransferases (HATs) or histone deacetylases (HDACs), respectively.
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Figure 3. Polycomb Group Complexes (PRCs) in OA: Polycomb repressive complex 1 (PRC1) and Polycomb repressive complex 2 (PRC2) are protein complexes that contribute to chromatin compaction to regulate development, cell proliferation, and differentiation. In OA, dysregulation of PRCs contributes to increased inflammation and aberrant Wnt pathway signaling activation, resulting in premature chondrocytes differentiation and accelerated chondrocyte hypertrophy differentiation.
Figure 3. Polycomb Group Complexes (PRCs) in OA: Polycomb repressive complex 1 (PRC1) and Polycomb repressive complex 2 (PRC2) are protein complexes that contribute to chromatin compaction to regulate development, cell proliferation, and differentiation. In OA, dysregulation of PRCs contributes to increased inflammation and aberrant Wnt pathway signaling activation, resulting in premature chondrocytes differentiation and accelerated chondrocyte hypertrophy differentiation.
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Figure 4. siRNA- and miRNA-targeted repression in OA. Small interfering RNAs (siRNAs) and microRNAs (miRNAs) and two types of non-coding RNAs (ncRNAS) that alter gene expression patterns via (A) post-translational repression or base pair complementarity (RNAi). siRNAs and miRNAs are known to target various aspects of OA pathology including (B) inflammation of chondrocytes and synovium, matrix degradation (enhanced enzymatic production), matrix anabolism (inhibition of anabolic expression) and chondrocyte apoptosis. Red line indicates siRNA or miRNA inclusion in the RNA-induced silencing complex (RISC).
Figure 4. siRNA- and miRNA-targeted repression in OA. Small interfering RNAs (siRNAs) and microRNAs (miRNAs) and two types of non-coding RNAs (ncRNAS) that alter gene expression patterns via (A) post-translational repression or base pair complementarity (RNAi). siRNAs and miRNAs are known to target various aspects of OA pathology including (B) inflammation of chondrocytes and synovium, matrix degradation (enhanced enzymatic production), matrix anabolism (inhibition of anabolic expression) and chondrocyte apoptosis. Red line indicates siRNA or miRNA inclusion in the RNA-induced silencing complex (RISC).
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Figure 5. circRNA- and lncRNA-targeted modulation in OA. circRNAs (A) and long non-coding RNAs (lncRNAs) (B) contribute to disease pathogenesis in OA through the dysregulation of chondrocyte proliferation and survival, altered anabolism and catabolism of the extracellular matrix (ECM) and through changes in inflammation.
Figure 5. circRNA- and lncRNA-targeted modulation in OA. circRNAs (A) and long non-coding RNAs (lncRNAs) (B) contribute to disease pathogenesis in OA through the dysregulation of chondrocyte proliferation and survival, altered anabolism and catabolism of the extracellular matrix (ECM) and through changes in inflammation.
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Ball, H.C.; Alejo, A.L.; Samson, T.K.; Alejo, A.M.; Safadi, F.F. Epigenetic Regulation of Chondrocytes and Subchondral Bone in Osteoarthritis. Life 2022, 12, 582. https://doi.org/10.3390/life12040582

AMA Style

Ball HC, Alejo AL, Samson TK, Alejo AM, Safadi FF. Epigenetic Regulation of Chondrocytes and Subchondral Bone in Osteoarthritis. Life. 2022; 12(4):582. https://doi.org/10.3390/life12040582

Chicago/Turabian Style

Ball, Hope C., Andrew L. Alejo, Trinity K. Samson, Amanda M. Alejo, and Fayez F. Safadi. 2022. "Epigenetic Regulation of Chondrocytes and Subchondral Bone in Osteoarthritis" Life 12, no. 4: 582. https://doi.org/10.3390/life12040582

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