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Epigenetic, microRNA and Long Non-Coding RNA Roles in Osteoporosis

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 July 2020) | Viewed by 27507

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Special Issue Editor

Dr. Gianluca Giavaresi

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Guest Editor

IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
Interests: degenerative and oncological orthopedic pathologies; osteoporosis; exosomes; miRNA and long non-coding RNA; molecular biology; regenerative medicine; biomaterials; biocompatibility and osteointegration

Special Issue Information

Dear Colleagues,

Osteoporosis is a complex multifactorial bone disorder, resulting from clinical, medical, behavioral, nutritional, and genetic factors. It results from the impairment of the balance between bone resorption by osteoclasts and bone formation by osteoblasts, leading to a high risk of bone fracture. The processes that maintain in balance the differentiation and the activity of osteoblasts and osteoclasts are controlled by specific genes and are finely regulated by endogenous and exogenous factors. Recently, epigenetic mechanisms, whose role in a number of biological processes is well documented (e.g., cell proliferation, cell differentiation, apoptosis, and cancer) have been demonstrated to be involved in bone metabolism, and their alterations might be implicated in the onset of osteoporosis.

The scope of this Special Issue is to investigate the role of epigenetic modifications, including DNA methylation, histone modifications, and the deregulation of miRNA-based pathways, in the pathogenesis of osteoporosis. A better understanding of the roles of epigenetic mechanisms in normal bone metabolism and in multifactorial bone disorders could help their translation into clinical practice, as well as for a better comprehension of disease pathogenesis.

Dr. Gianluca Giavaresi
Guest Editor

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Keywords

bone metabolism
epigenetics
long non-coding RNA
microRNA
osteoblast
osteoclast
osteocyte
osteoporosis

Published Papers (7 papers)

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Research

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18 pages, 5351 KiB

Open AccessArticle

METTL3 Modulates Osteoclast Differentiation and Function by Controlling RNA Stability and Nuclear Export

by Di Li, Luhui Cai, Runsha Meng, Zhihui Feng and Qiong Xu

Int. J. Mol. Sci. 2020, 21(5), 1660; https://doi.org/10.3390/ijms21051660 - 28 Feb 2020

Cited by 68 | Viewed by 4720

Abstract

Osteoclast differentiation and function are crucial for maintaining bone homeostasis and preserving skeletal integrity. N6-methyladenosine (m⁶A) is an abundant mRNA modification that has recently been shown to be important in regulating cell lineage differentiation. Nevertheless, the effect of m⁶A on osteoclast differentiation remains unknown. In the present study, we observed that the m⁶A level and methyltransferase METTL3 expression increased during osteoclast differentiation. Mettl3 knockdown resulted in an increased size but a decreased bone-resorbing ability of osteoclasts. The expression of osteoclast-specific genes (Nfatc1, c-Fos, Ctsk, Acp5 and Dcstamp) was inhibited by Mettl3 depletion, while the expression of the cellular fusion-specific gene Atp6v0d2 was upregulated. Mechanistically, Mettl3 knockdown elevated the mRNA stability of Atp6v0d2 and the same result was obtained when the m⁶A-binding protein YTHDF2 was silenced. Moreover, the phosphorylation levels of key molecules in the MAPK, NF-κB and PI3K-AKT signaling pathways were reduced upon Mettl3 deficiency. Depletion of Mettl3 maintained the retention of Traf6 mRNA in the nucleus and reduced the protein levels of TRAF6. Taken together, our data suggest that METTL3 regulates osteoclast differentiation and function through different mechanisms involving Atp6v0d2 mRNA degradation mediated by YTHDF2 and Traf6 mRNA nuclear export. These findings elucidate the molecular basis of RNA epigenetic regulation in osteoclast development. Full article

(This article belongs to the Special Issue Epigenetic, microRNA and Long Non-Coding RNA Roles in Osteoporosis)

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Review

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21 pages, 1974 KiB

Open AccessReview

The Role of Epigenomics in Osteoporosis and Osteoporotic Vertebral Fracture

by Kyoung-Tae Kim, Young-Seok Lee and Inbo Han

Int. J. Mol. Sci. 2020, 21(24), 9455; https://doi.org/10.3390/ijms21249455 - 11 Dec 2020

Cited by 14 | Viewed by 3057

Abstract

Osteoporosis is a complex multifactorial condition of the musculoskeletal system. Osteoporosis and osteoporotic vertebral fracture (OVF) are associated with high medical costs and can lead to poor quality of life. Genetic factors are important in determining bone mass and structure, as well as any predisposition for bone degradation and OVF. However, genetic factors are not enough to explain osteoporosis development and OVF occurrence. Epigenetics describes a mechanism for controlling gene expression and cellular processes without altering DNA sequences. The main mechanisms in epigenetics are DNA methylation, histone modifications, and non-coding RNAs (ncRNAs). Recently, alterations in epigenetic mechanisms and their activity have been associated with osteoporosis and OVF. Here, we review emerging evidence that epigenetics contributes to the machinery that can alter DNA structure, gene expression, and cellular differentiation during physiological and pathological bone remodeling. A progressive understanding of normal bone metabolism and the role of epigenetic mechanisms in multifactorial osteopathy can help us better understand the etiology of the disease and convert this information into clinical practice. A deep understanding of these mechanisms will help in properly coordinating future individual treatments of osteoporosis and OVF. Full article

(This article belongs to the Special Issue Epigenetic, microRNA and Long Non-Coding RNA Roles in Osteoporosis)

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21 pages, 1630 KiB

Open AccessReview

The Role of Extracellular Vesicles (EVs) in the Epigenetic Regulation of Bone Metabolism and Osteoporosis

by Maurizio Muraca and Alfredo Cappariello

Int. J. Mol. Sci. 2020, 21(22), 8682; https://doi.org/10.3390/ijms21228682 - 17 Nov 2020

Cited by 26 | Viewed by 3358

Abstract

Extracellular vesicles (EVs) are complex phospholipidic structures actively released by cells. EVs are recognized as powerful means of intercellular communication since they contain many signaling molecules (including lipids, proteins, and nucleic acids). In parallel, changes in epigenetic processes can lead to changes in gene function and finally lead to disease onset and progression. Recent breakthroughs have revealed the complex roles of non-coding RNAs (microRNAs (miRNAs) and long non-coding RNAs (lncRNAs)) in epigenetic regulation. Moreover, a substantial body of evidence demonstrates that non-coding RNAs can be shuttled among the cells and tissues via EVs, allowing non-coding RNAs to reach distant cells and exert systemic effects. Resident bone cells, including osteoclasts, osteoblasts, osteocytes, and endothelial cells, are tightly regulated by non-coding RNAs, and many of them can be exported from the cells to neighboring ones through EVs, triggering pathological conditions. For these reasons, researchers have also started to exploit EVs as a theranostic tool to address osteoporosis. In this review, we summarize some recent findings regarding the EVs’ involvement in the fine regulation of non-coding RNAs in the context of bone metabolism and osteoporosis. Full article

(This article belongs to the Special Issue Epigenetic, microRNA and Long Non-Coding RNA Roles in Osteoporosis)

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15 pages, 1079 KiB

Open AccessReview

Epigenetic Regulators Involved in Osteoclast Differentiation

by Kristina Astleford, Emily Campbell, Andrew Norton and Kim C. Mansky

Int. J. Mol. Sci. 2020, 21(19), 7080; https://doi.org/10.3390/ijms21197080 - 25 Sep 2020

Cited by 14 | Viewed by 4698

Abstract

Age related changes to the skeleton, such as osteoporosis, increase the risk of fracture and morbidity in the elderly population. In osteoporosis, bone remodeling becomes unbalanced with an increase in bone resorption and a decrease in bone formation. Osteoclasts are large multinucleated cells that secrete acid and proteases to degrade and resorb bone. Understanding the molecular mechanisms that regulate osteoclast differentiation and activity will provide insight as to how hyper-active osteoclasts lead to pathological bone loss, contributing to diseases such as osteoporosis. Reversible modifications to the DNA such as histone acetylation, methylation, phosphorylation and ubiquitylation alters the access of transcriptional machinery to DNA and regulates gene expression and osteoclast differentiation and activity. It is critical for the management of bone related diseases to understand the role of these chromatin modifying proteins during osteoclast differentiation, as potential therapies targeting these proteins are currently under development. Full article

(This article belongs to the Special Issue Epigenetic, microRNA and Long Non-Coding RNA Roles in Osteoporosis)

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21 pages, 1117 KiB

Open AccessReview

Circulating MicroRNAs as Novel Biomarkers for Osteoporosis and Fragility Fracture Risk: Is There a Use in Assessment Risk?

by Simone Ciuffi, Simone Donati, Francesca Marini, Gaia Palmini, Ettore Luzi and Maria Luisa Brandi

Int. J. Mol. Sci. 2020, 21(18), 6927; https://doi.org/10.3390/ijms21186927 - 21 Sep 2020

Cited by 10 | Viewed by 2481

Abstract

Osteoporosis is a multifactorial skeletal disease that is associated with both bone mass decline and microstructure damage. The fragility fractures—especially those affecting the femur—that embody the clinical manifestation of this pathology continue to be a great medical and socioeconomic challenge worldwide. The currently available diagnostic tools, such as dual energy X-ray absorptiometry, Fracture Risk Assessment Tool (FRAX) score, and bone turnover markers, show limited specificity and sensitivity; therefore, the identification of alternative approaches is necessary. As a result of their advantageous features, such as non-invasiveness, biofluid stability, and easy detection, circulating cell-free miRs are promising new potential biomarkers for the diagnosis of osteoporosis and low-traumatic fracture risk assessment. However, due to the absence of both standardized pre-analytical, analytical, and post-analytical protocols for their measurement and universally accepted guidelines for diagnostic use, their clinical utility is limited. The aim of this review was to record all the data currently available in the literature concerning the use of circulating microRNAs as both potential biomarkers for osteoporosis diagnosis and fragility fracture risk evaluation, and group them according to the experimental designs, in order to support a more conscious choice of miRs for future research in this field. Full article

(This article belongs to the Special Issue Epigenetic, microRNA and Long Non-Coding RNA Roles in Osteoporosis)

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16 pages, 546 KiB

Open AccessReview

Epigenetic Regulation of Skeletal Tissue Integrity and Osteoporosis Development

by Yu-Shan Chen, Wei-Shiung Lian, Chung-Wen Kuo, Huei-Jing Ke, Shao-Yu Wang, Pei-Chen Kuo, Holger Jahr and Feng-Sheng Wang

Int. J. Mol. Sci. 2020, 21(14), 4923; https://doi.org/10.3390/ijms21144923 - 12 Jul 2020

Cited by 13 | Viewed by 3705

Abstract

Bone turnover is sophisticatedly balanced by a dynamic coupling of bone formation and resorption at various rates. The orchestration of this continuous remodeling of the skeleton further affects other skeletal tissues through organ crosstalk. Chronic excessive bone resorption compromises bone mass and its porous microstructure as well as proper biomechanics. This accelerates the development of osteoporotic disorders, a leading cause of skeletal degeneration-associated disability and premature death. Bone-forming cells play important roles in maintaining bone deposit and osteoclastic resorption. A poor organelle machinery, such as mitochondrial dysfunction, endoplasmic reticulum stress, and defective autophagy, etc., dysregulates growth factor secretion, mineralization matrix production, or osteoclast-regulatory capacity in osteoblastic cells. A plethora of epigenetic pathways regulate bone formation, skeletal integrity, and the development of osteoporosis. MicroRNAs inhibit protein translation by binding the 3′-untranslated region of mRNAs or promote translation through post-transcriptional pathways. DNA methylation and post-translational modification of histones alter the chromatin structure, hindering histone enrichment in promoter regions. MicroRNA-processing enzymes and DNA as well as histone modification enzymes catalyze these modifying reactions. Gain and loss of these epigenetic modifiers in bone-forming cells affect their epigenetic landscapes, influencing bone homeostasis, microarchitectural integrity, and osteoporotic changes. This article conveys productive insights into biological roles of DNA methylation, microRNA, and histone modification and highlights their interactions during skeletal development and bone loss under physiological and pathological conditions. Full article

(This article belongs to the Special Issue Epigenetic, microRNA and Long Non-Coding RNA Roles in Osteoporosis)

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18 pages, 613 KiB

Open AccessReview

The Role of Micro RNA and Long-Non-Coding RNA in Osteoporosis

by Nai-Yu Ko, Li-Ru Chen and Kuo-Hu Chen

Int. J. Mol. Sci. 2020, 21(14), 4886; https://doi.org/10.3390/ijms21144886 - 10 Jul 2020

Cited by 57 | Viewed by 5102

Abstract

Osteoporosis is a major concern worldwide and can be attributed to an imbalance between osteoblastic bone formation and osteoclastic bone resorption due to the natural aging process. Heritable factors account for 60–80% of optimal bone mineralization; however, the finer details of pathogenesis remain to be elucidated. Micro RNA (miRNA) and long-non-coding RNA (lncRNA) are two targets that have recently come into the spotlight due to their ability to control gene expression at the post-transcriptional level and provide epigenetic modification. miRNAs are a class of non-coding RNAs that are approximately 18–25 nucleotides long. It is thought that up to 60% of human protein-coding genes may be regulated by miRNAs. They have been found to regulate gene expression that controls osteoblast-dependent bone formation and osteoclast-related bone remodeling. lncRNAs are highly structured RNA transcripts longer than 200 nucleotides that do not translate into proteins. They have very complex secondary and tertiary structures and the same degradation processes as messenger RNAs. The fact that they have a rapid turnover is due to their sponge function in binding the miRNAs that lead to a degradation of the lncRNA itself. They can act as signaling, decoy, and framework molecules, or as primers. Current evidence suggests that lncRNAs can act as chromatin and transcriptional as well as post-transcriptional regulators. With regards to osteoporosis, lncRNA is thought to be involved in the proliferation, apoptosis, and inflammatory response of the bone. This review, which is based on a systematic appraisal of the current literature, provides current molecular and genetic opinions on the roles of miRNAs and lncRNAs in osteoporosis. Further research into the epigenetic modification and the regulatory roles of these molecules will bring us closer to potential disease-modifying treatment for osteoporosis. However, more issues regarding the detailed actions of miRNAs and lncRNAs in osteoporosis remain unknown and controversial and warrant future investigation. Full article

(This article belongs to the Special Issue Epigenetic, microRNA and Long Non-Coding RNA Roles in Osteoporosis)

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