MEF2C regulates osteoclastogenesis and pathologic bone resorption via c-FOS.

TitleMEF2C regulates osteoclastogenesis and pathologic bone resorption via c-FOS.
Publication TypeJournal Article
Year of Publication2021
AuthorsFujii T, Murata K, Mun S-H, Bae S, Lee YJi, Pannellini T, Kang K, Oliver D, Park-Min K-H, Ivashkiv LB
JournalBone Res
Volume9
Issue1
Pagination4
Date Published2021 Jan 11
ISSN2095-4700
Abstract

Osteoporosis is a metabolic bone disease with dysregulated coupling between bone resorption and bone formation, which results in decreased bone mineral density. The MEF2C locus, which encodes the transcription factor MADS box transcription enhancer factor 2, polypeptide C (MEF2C), is strongly associated with adult osteoporosis and osteoporotic fractures. Although the role of MEF2C in bone and cartilage formation by osteoblasts, osteocytes, and chondrocytes has been studied, the role of MEF2C in osteoclasts, which mediate bone resorption, remains unclear. In this study, we identified MEF2C as a positive regulator of human and mouse osteoclast differentiation. While decreased MEF2C expression resulted in diminished osteoclastogenesis, ectopic expression of MEF2C enhanced osteoclast generation. Using transcriptomic and bioinformatic approaches, we found that MEF2C promotes the RANKL-mediated induction of the transcription factors c-FOS and NFATc1, which play a key role in osteoclastogenesis. Mechanistically, MEF2C binds to FOS regulatory regions to induce c-FOS expression, leading to the activation of NFATC1 and downstream osteoclastogenesis. Inducible deletion of Mef2c in mice resulted in increased bone mass under physiological conditions and protected mice from bone erosion by diminishing osteoclast formation in K/BxN serum induced arthritis, a murine model of inflammatory arthritis. Our findings reveal direct regulation of osteoclasts by MEF2C, thus adding osteoclasts as a cell type in which altered MEF2C expression or function can contribute to pathological bone remodeling.

DOI10.1038/s41413-020-00120-2
Alternate JournalBone Res
PubMed ID33424022
PubMed Central IDPMC7797478
Grant ListR01 AI044938 / AI / NIAID NIH HHS / United States
R01 DE019420 / DE / NIDCR NIH HHS / United States
5R01 AR073156 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) /
5R01 AR069562 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) /
Related Faculty: 
Tania Pannellini, M.D., Ph.D.

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