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 MAD...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.展开更多
Mutation of the MAPK7 gene was related to human scoliosis.Mapk7 regulated the development of limb bones and skulls in mice.However,the role of MAPK7 in vertebral development is still unclear.In this study,we construct...Mutation of the MAPK7 gene was related to human scoliosis.Mapk7 regulated the development of limb bones and skulls in mice.However,the role of MAPK7 in vertebral development is still unclear.In this study,we constructed Col2a1-cre;Mapk7 f/f transgenic mouse model to delete Mapk7 in cartilage,which displayed kyphosis and osteopenia.Mechanistically,Mapk7 loss decreased MEF2C expression and thus activated PTEN to oppose PI3K/AKT signaling in vertebral growth plate chondrocytes,which impaired chondrocyte hypertrophy and attenuated vertebral ossification.In vivo,systemic pharmacological activation of AKT rescued impaired chondrocyte hypertrophy and alleviated mouse vertebral defects caused by Mapk7 deficiency.Our study firstly clarified the mechanism by which MAPK7 was involved in vertebral development,which might contribute to understanding the pathology of spinal deformity and provide a basis for the treatment of developmental disorders of the spine.展开更多
文摘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.
基金supported by the National Natural Science Foundation of China(No.92068105,82172376,82072385).
文摘Mutation of the MAPK7 gene was related to human scoliosis.Mapk7 regulated the development of limb bones and skulls in mice.However,the role of MAPK7 in vertebral development is still unclear.In this study,we constructed Col2a1-cre;Mapk7 f/f transgenic mouse model to delete Mapk7 in cartilage,which displayed kyphosis and osteopenia.Mechanistically,Mapk7 loss decreased MEF2C expression and thus activated PTEN to oppose PI3K/AKT signaling in vertebral growth plate chondrocytes,which impaired chondrocyte hypertrophy and attenuated vertebral ossification.In vivo,systemic pharmacological activation of AKT rescued impaired chondrocyte hypertrophy and alleviated mouse vertebral defects caused by Mapk7 deficiency.Our study firstly clarified the mechanism by which MAPK7 was involved in vertebral development,which might contribute to understanding the pathology of spinal deformity and provide a basis for the treatment of developmental disorders of the spine.
