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Molecular Basis of Osteoclast Differentiation and Activation
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Molecular Basis of Osteoclast Differentiation and Activation

A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: closed (30 November 2020) | Viewed by 55920

Special Issue Editor

Dr. Kyung Hyun Park-Min

E-Mail Website
Guest Editor
1. Arthritis and Tissue Degeneration Program and the David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY 10021, USA
2. Department of Medicine, Weill Cornell Medicine, New York, NY 10021, USA
Interests: osteoimmunology; osteoclasts; metabolism; epigenetics; osteoporosis; avascular necrosis

Special Issue Information

Dear Colleagues,

As the only cells that can efficiently resorb bone, osteoclasts play a crucial role in maintaining bone health, differentiating from myeloid lineage precursor cells under the influence of a variety of cytokines and local factors. Chief among these are the macrophage colony stimulating factor (M-CSF) and receptor activator of NF-kB ligand (RANKL), which initiates osteoclast differentiation and serves as a critical factor for osteoclastogenesis and osteoclast activity. Over the past few decades following the initial discovery of RANKL, multiple signals that contribute to the differentiation and activity of osteoclasts have been identified. These complicated signaling networks provide multilayer regulations of osteoclasts; achieving a better understanding of the mechanisms involved in such networks can lead to the development of new therapeutic strategies to prevent or halt the pathogenesis of bone erosion, as well as suffering from its debilitating effects.

Thus, this special issue aims to provide an expansive overview of the intricate interplay between RANKL and the various signals that drive osteoclast differentiation and activity under physiological conditions. This issue also examines how these integrations can be modified under pathological conditions. With further discussion of the novel aspects of regulatory mechanisms that underlie osteoclast differentiation and function, I hope the research community can find value in our pursuit to broaden current knowledge of the spectrum of therapeutic targets that regulate osteoclasts in various disease settings.

Dr. Kyung Hyun Park-Min
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Osteoclasts
  • Osteoclast precursor cells
  • Signaling pathways
  • RANKL
  • Osteoclastoenesis
  • Bone resorption

Published Papers (8 papers)

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Research

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11 pages, 1299 KiB  
Article
Role of Synovial Exosomes in Osteoclast Differentiation in Inflammatory Arthritis
by Ji Eun Song, Ji Soo Kim, Ji Hye Shin, Ki Won Moon, Jin Kyun Park, Kyong Soo Park and Eun Young Lee
Cells 2021, 10(1), 120; https://doi.org/10.3390/cells10010120 - 10 Jan 2021
Cited by 20 | Viewed by 3236
Abstract
This study aimed to investigate the characteristics of exosomes isolated from synovial fluid and their role in osteoclast differentiation in different types of inflammatory arthritis. Exosomes isolated from synovial fluid of rheumatoid arthritis (RA), ankylosing spondylitis (AS), gout, and osteoarthritis (OA) patients were [...] Read more.
This study aimed to investigate the characteristics of exosomes isolated from synovial fluid and their role in osteoclast differentiation in different types of inflammatory arthritis. Exosomes isolated from synovial fluid of rheumatoid arthritis (RA), ankylosing spondylitis (AS), gout, and osteoarthritis (OA) patients were co-incubated with CD14+ mononuclear cells from healthy donors without macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor kappa-B ligand (RANKL). Osteoclast differentiation was evaluated via tartrate-resistant acid phosphatase (TRAP) staining and activity and F-actin ring formation. RANKL expression on synovial exosomes was assessed using flow cytometry and an enzyme-linked immunosorbent assay (ELISA). Synovial exosomes were the lowest in OA patients; these induced osteoclastogenesis in the absence of M-CSF and RANKL. Osteoclastogenesis was significantly higher with more exosomes in RA (p = 0.030) than in OA patients, but not in AS or gout patients. On treating macrophages with a specified number of synovial exosomes from RA/AS patients, exosomes induced greater osteoclastogenesis in RA than in AS patients. Synovial exosomal RANKL levels were significantly higher in RA (p = 0.035) than in AS patients. Synovial exosome numbers vary with the type of inflammatory arthritis. Synovial exosomes from RA patients may bear the disease-specific “synovial signature of osteoclastogenesis.” Full article
(This article belongs to the Special Issue Molecular Basis of Osteoclast Differentiation and Activation)
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14 pages, 4783 KiB  
Article
Implication of the Association of Fibrinogen Citrullination and Osteoclastogenesis in Bone Destruction in Rheumatoid Arthritis
by Ji Soo Kim, Mikyung Choi, Ji Yong Choi, Joo Yeon Kim, Jeong Yeon Kim, Jin-Su Song, Lionel B. Ivashkiv and Eun Young Lee
Cells 2020, 9(12), 2720; https://doi.org/10.3390/cells9122720 - 20 Dec 2020
Cited by 14 | Viewed by 2677
Abstract
Immune complexes containing citrullinated fibrinogen are present in the sera and synovium of rheumatoid arthritis patients and potentially contribute to synovitis. However, fibrinogen can inhibit the osteoclastogenesis of precursor cells. We investigated the direct effect of citrullinated fibrinogen on osteoclastogenesis to understand the [...] Read more.
Immune complexes containing citrullinated fibrinogen are present in the sera and synovium of rheumatoid arthritis patients and potentially contribute to synovitis. However, fibrinogen can inhibit the osteoclastogenesis of precursor cells. We investigated the direct effect of citrullinated fibrinogen on osteoclastogenesis to understand the role of citrullination on bone erosion of rheumatoid arthritis patients. We evaluated the fibrinogen citrullination sites using mass spectrometry and quantified osteoclast-related protein and gene expression levels by Western blotting, microarray, and real-time polymerase chain reaction. Differences in spectral peaks were noted between fibrinogen and citrullinated fibrinogen at five sites in α-chains, two sites in β-chains, and one site in a γ-chain. Transcriptome changes induced by fibrinogen and citrullinated fibrinogen were identified and differentially expressed genes grouped into three distinctive modules. Fibrinogen was then citrullinated in vitro using peptidylarginine deiminase. When increasing doses of soluble fibrinogen and citrullinated fibrinogen were applied to human CD14+ monocytes, citrullination restored osteoclastogenesis-associated changes, including NF-ATc1 and ß3-integrin. Finally, citrullination rescued the number of osteoclasts by restoring fibrinogen-induced suppression of osteoclastogenesis. Taken together, the results indicate that the inhibitory function of fibrinogen on osteoclastogenesis is reversed by citrullination and suggest that citrullinated fibrinogen may contribute to erosive bone destruction in rheumatoid arthritis. Full article
(This article belongs to the Special Issue Molecular Basis of Osteoclast Differentiation and Activation)
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20 pages, 5719 KiB  
Article
NRF2 Is an Upstream Regulator of MYC-Mediated Osteoclastogenesis and Pathological Bone Erosion
by Peter Sang Uk Park, Se Hwan Mun, Steven L. Zeng, Haemin Kim, Seyeon Bae and Kyung-Hyun Park-Min
Cells 2020, 9(9), 2133; https://doi.org/10.3390/cells9092133 - 21 Sep 2020
Cited by 12 | Viewed by 3399
Abstract
Osteoclasts are the sole bone-resorbing cells that play an essential role in homeostatic bone remodeling and pathogenic bone destruction such as inflammatory arthritis. Pharmacologically targeting osteoclasts has been a promising approach to alleviating bone disease, but there remains room for improvement in mitigating [...] Read more.
Osteoclasts are the sole bone-resorbing cells that play an essential role in homeostatic bone remodeling and pathogenic bone destruction such as inflammatory arthritis. Pharmacologically targeting osteoclasts has been a promising approach to alleviating bone disease, but there remains room for improvement in mitigating drug side effects and enhancing cell specificity. Recently, we demonstrated the crucial role of MYC and its downstream effectors in driving osteoclast differentiation. Despite these advances, upstream regulators of MYC have not been well defined. In this study, we identify nuclear factor erythroid 2-related factor 2 (NRF2), a transcription factor known to regulate the expression of phase II antioxidant enzymes, as a novel upstream regulator of MYC. NRF2 negatively regulates receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis through the ERK and p38 signaling-mediated suppression of MYC transcription. Furthermore, the ablation of MYC in osteoclasts reverses the enhanced osteoclast differentiation and activity in NRF2 deficiency in vivo and in vitro in addition to protecting NRF2-deficient mice from pathological bone loss in a murine model of inflammatory arthritis. Our findings indicate that this novel NRF2-MYC axis could be instrumental for the fine-tuning of osteoclast formation and provides additional ways in which osteoclasts could be therapeutically targeted to prevent pathological bone erosion. Full article
(This article belongs to the Special Issue Molecular Basis of Osteoclast Differentiation and Activation)
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Review

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20 pages, 1530 KiB  
Review
Regulation of Osteoclast Differentiation and Activity by Lipid Metabolism
by Haemin Kim, Brian Oh and Kyung-Hyun Park-Min
Cells 2021, 10(1), 89; https://doi.org/10.3390/cells10010089 - 07 Jan 2021
Cited by 42 | Viewed by 5557
Abstract
Bone is a dynamic tissue and is constantly being remodeled by bone cells. Metabolic reprogramming plays a critical role in the activation of these bone cells and skeletal metabolism, which fulfills the energy demand for bone remodeling. Among various metabolic pathways, the importance [...] Read more.
Bone is a dynamic tissue and is constantly being remodeled by bone cells. Metabolic reprogramming plays a critical role in the activation of these bone cells and skeletal metabolism, which fulfills the energy demand for bone remodeling. Among various metabolic pathways, the importance of lipid metabolism in bone cells has long been appreciated. More recent studies also establish the link between bone loss and lipid-altering conditions—such as atherosclerotic vascular disease, hyperlipidemia, and obesity—and uncover the detrimental effect of fat accumulation on skeletal homeostasis and increased risk of fracture. Targeting lipid metabolism with statin, a lipid-lowering drug, has been shown to improve bone density and quality in metabolic bone diseases. However, the molecular mechanisms of lipid-mediated regulation in osteoclasts are not completely understood. Thus, a better understanding of lipid metabolism in osteoclasts can be used to harness bone cell activity to treat pathological bone disorders. This review summarizes the recent developments of the contribution of lipid metabolism to the function and phenotype of osteoclasts. Full article
(This article belongs to the Special Issue Molecular Basis of Osteoclast Differentiation and Activation)
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11 pages, 784 KiB  
Review
The Role of Aryl-Hydrocarbon Receptor (AhR) in Osteoclast Differentiation and Function
by Robin Park, Shreya Madhavaram and Jong Dae Ji
Cells 2020, 9(10), 2294; https://doi.org/10.3390/cells9102294 - 14 Oct 2020
Cited by 19 | Viewed by 4604
Abstract
Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that plays a crucial role in bone remodeling through altering the interplay between bone-forming osteoblasts and bone-resorbing osteoclasts. While effects of AhR signaling in osteoblasts are well understood, the role and mechanism of AhR [...] Read more.
Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that plays a crucial role in bone remodeling through altering the interplay between bone-forming osteoblasts and bone-resorbing osteoclasts. While effects of AhR signaling in osteoblasts are well understood, the role and mechanism of AhR signaling in regulating osteoclastogenesis is not widely understood. AhR, when binding with exogenous ligands (environmental pollutants such as polycylic aryl hydrocarbon (PAH), dioxins) or endogenous ligand indoxyl-sulfate (IS), has dual functions that are mediated by the nature of the binding ligand, binding time, and specific pathways of distinct ligands. In this review, AhR is discussed with a focus on (i) the role of AhR in osteoclast differentiation and function and (ii) the mechanisms of AhR signaling in inhibiting or promoting osteoclastogenesis. These findings facilitate an understanding of the role of AhR in the functional regulation of osteoclasts and in osteoclast-induced bone destructive conditions such as rheumatoid arthritis and cancer. Full article
(This article belongs to the Special Issue Molecular Basis of Osteoclast Differentiation and Activation)
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14 pages, 1125 KiB  
Review
Multitasking by the OC Lineage during Bone Infection: Bone Resorption, Immune Modulation, and Microbial Niche
by Philip M. Roper, Christine Shao and Deborah J. Veis
Cells 2020, 9(10), 2157; https://doi.org/10.3390/cells9102157 - 24 Sep 2020
Cited by 17 | Viewed by 2696
Abstract
Bone infections, also known as infectious osteomyelitis, are accompanied by significant inflammation, osteolysis, and necrosis. Osteoclasts (OCs) are the bone-resorbing cells that work in concert with osteoblasts and osteocytes to properly maintain skeletal health and are well known to respond to inflammation by [...] Read more.
Bone infections, also known as infectious osteomyelitis, are accompanied by significant inflammation, osteolysis, and necrosis. Osteoclasts (OCs) are the bone-resorbing cells that work in concert with osteoblasts and osteocytes to properly maintain skeletal health and are well known to respond to inflammation by increasing their resorptive activity. OCs have typically been viewed merely as effectors of pathologic bone resorption, but recent evidence suggests they may play an active role in the progression of infections through direct effects on pathogens and via the immune system. This review discusses the host- and pathogen-derived factors involved in the in generation of OCs during infection, the crosstalk between OCs and immune cells, and the role of OC lineage cells in the growth and survival of pathogens, and highlights unanswered questions in the field. Full article
(This article belongs to the Special Issue Molecular Basis of Osteoclast Differentiation and Activation)
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7 pages, 604 KiB  
Review
Sexual Dimorphism in Osteoclasts
by Joseph Lorenzo
Cells 2020, 9(9), 2086; https://doi.org/10.3390/cells9092086 - 12 Sep 2020
Cited by 12 | Viewed by 2961
Abstract
Osteoclasts are the principal mediators of bone resorption. They form through the fusion of mononuclear precursor cells under the principal influence of the cytokines macrophage colony stimulating factor (M-CSF, aka CSF-1) and receptor activator of NF-κB ligand (RANKL, aka TNFSF11). Sexual dimorphism in [...] Read more.
Osteoclasts are the principal mediators of bone resorption. They form through the fusion of mononuclear precursor cells under the principal influence of the cytokines macrophage colony stimulating factor (M-CSF, aka CSF-1) and receptor activator of NF-κB ligand (RANKL, aka TNFSF11). Sexual dimorphism in the development of the skeleton and in the incidence of skeletal diseases is well described. In general, females, at any given age, have a lower bone mass than males. The reasons for the differences in the bone mass of the skeleton between women and men at various ages, and the incidence of certain metabolic bone diseases, are multitude, and include the actions of sex steroids, genetics, age, environment and behavior. All of these influence the rate that osteoclasts form, resorb and die, and frequently produce different effects in females and males. Hence, a variety of factors are responsible for the sexual dimorphism of the skeleton and the activity of osteoclasts in bone. This review will provide an overview of what is currently known about these factors and their effects on osteoclasts. Full article
(This article belongs to the Special Issue Molecular Basis of Osteoclast Differentiation and Activation)
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14 pages, 835 KiB  
Review
Osteoblast-Osteoclast Communication and Bone Homeostasis
by Jung-Min Kim, Chujiao Lin, Zheni Stavre, Matthew B. Greenblatt and Jae-Hyuck Shim
Cells 2020, 9(9), 2073; https://doi.org/10.3390/cells9092073 - 10 Sep 2020
Cited by 497 | Viewed by 29898
Abstract
Bone remodeling is tightly regulated by a cross-talk between bone-forming osteoblasts and bone-resorbing osteoclasts. Osteoblasts and osteoclasts communicate with each other to regulate cellular behavior, survival and differentiation through direct cell-to-cell contact or through secretory proteins. A direct interaction between osteoblasts and osteoclasts [...] Read more.
Bone remodeling is tightly regulated by a cross-talk between bone-forming osteoblasts and bone-resorbing osteoclasts. Osteoblasts and osteoclasts communicate with each other to regulate cellular behavior, survival and differentiation through direct cell-to-cell contact or through secretory proteins. A direct interaction between osteoblasts and osteoclasts allows bidirectional transduction of activation signals through EFNB2-EPHB4, FASL-FAS or SEMA3A-NRP1, regulating differentiation and survival of osteoblasts or osteoclasts. Alternatively, osteoblasts produce a range of different secretory molecules, including M-CSF, RANKL/OPG, WNT5A, and WNT16, that promote or suppress osteoclast differentiation and development. Osteoclasts also influence osteoblast formation and differentiation through secretion of soluble factors, including S1P, SEMA4D, CTHRC1 and C3. Here we review the current knowledge regarding membrane bound- and soluble factors governing cross-talk between osteoblasts and osteoclasts. Full article
(This article belongs to the Special Issue Molecular Basis of Osteoclast Differentiation and Activation)
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