MEF2C regulates osteoclastogenesis and pathologic bone resorption via c-FOS.
Takayuki FujiiKoichi MurataSe-Hwan MunSeyeon BaeYe Ji LeeTannia PannelliniKyuho KangDavid OliverKyung Hyung Park-MinLionel B IvashkivPublished in: Bone research (2021)
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.
Keyphrases
- bone loss
- bone mineral density
- transcription factor
- postmenopausal women
- body composition
- poor prognosis
- binding protein
- endothelial cells
- genome wide
- adipose tissue
- immune response
- dna methylation
- bone regeneration
- rectal cancer
- locally advanced
- nuclear factor
- toll like receptor
- induced pluripotent stem cells
- genome wide association study