Activation-induced cell death （AICD） of immune cells is widely believed to be crucial for the regulation of immune responses. Although macrophage apoptosis has been observed under a variety of pathological condition...Activation-induced cell death （AICD） of immune cells is widely believed to be crucial for the regulation of immune responses. Although macrophage apoptosis has been observed under a variety of pathological conditions, questions as to whether there is AICD ofmacrophages and how macrophage life span is regulated have not been well addressed. AICD in macrophages requires two signals. One is cell activation triggered by LPS or other bacterial components. The other is an event that exists in AICD-susceptible （primed） but not unsusceptible （resting） macrophages. Here we show that RAW264.7 cell is susceptible to LPS stimulation when it is primed with Salmonella typhimurium, type 5 adenovirus （Ad5） or IFN-γ. We found that the stability of the transcription factor MEF2C is increased in primed RAW264.7 cell. Transfection of a dominant negative form of MEF2C protects primed macrophage from cell death triggered by LPS. Our data demonstrate that the increase of MEF2C protein stability is a key factor in the AICD of macrophage.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
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
Background:MicroRNAs(miRNAs)are endogenous non-coding RNAS that regulate gene expression at the post-transcriptional level and are key modulators in neurodegenerative diseases.Overexpressed miRNAs play an important ro...Background:MicroRNAs(miRNAs)are endogenous non-coding RNAS that regulate gene expression at the post-transcriptional level and are key modulators in neurodegenerative diseases.Overexpressed miRNAs play an important role in amyotrophic lateral sclerosis(ALS);however,the pathogenic mechanisms of deregulated miRNAS are still unclear.Methods:We aimed to assess the dysfunction of RNAS or miRNAs in fALS(SOD1 mutations).We compared the RNA-seq of subcellular fractions in NSC-34 WT(hSOD1)and MT(hSOD1(G93A))cells to find altered RNAs or miRNAs.We identified that Hif1a and Mef2c were upregulated,and Mctp1 and Rarb were downregulated in the cytoplasm of NSC-34 MT cells.Results:SOD1 mutations decreased the level of miR-18b-5p.Induced Hif1a which is the target for miR-18b increased Mef2c expression as a transcription factor.Mef2c upregulated miR-206 as a transcription factor.Inhibition of Mctp1 and Rarb,which are targets of miR-206,induced intracellular Ca^2+ levels and reduced cell differentiation,respectively.The miR-18b-5p pathway was also observed in G93A Tg mice,fALS(G86S)patient,and iPSC-derived motor neurons from fALS(G17S)patient.Conclusions:Our data indicate that SOD1 mutation decreases miR-18b-5p,which sequentially regulates Hif1a,Mef2c,miR-206,Mctp1 and Rarb in fALS-linked SOD1 mutation.These results provide new insights into the downregulation of miR-18b-5p-dependent pathogenic mechanisms of ALS.展开更多
基金a grant （No. 30330260） from National Natural Science Foundation of China.
文摘Activation-induced cell death （AICD） of immune cells is widely believed to be crucial for the regulation of immune responses. Although macrophage apoptosis has been observed under a variety of pathological conditions, questions as to whether there is AICD ofmacrophages and how macrophage life span is regulated have not been well addressed. AICD in macrophages requires two signals. One is cell activation triggered by LPS or other bacterial components. The other is an event that exists in AICD-susceptible （primed） but not unsusceptible （resting） macrophages. Here we show that RAW264.7 cell is susceptible to LPS stimulation when it is primed with Salmonella typhimurium, type 5 adenovirus （Ad5） or IFN-γ. We found that the stability of the transcription factor MEF2C is increased in primed RAW264.7 cell. Transfection of a dominant negative form of MEF2C protects primed macrophage from cell death triggered by LPS. Our data demonstrate that the increase of MEF2C protein stability is a key factor in the AICD of macrophage.
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.
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This research was supported by the Brain Research Program through the National Research Foundation of Korea(NRF)funded by the Ministry of Science and ICT(2017M3C7A102536521 and 2018R1A5A202596413).
文摘Background:MicroRNAs(miRNAs)are endogenous non-coding RNAS that regulate gene expression at the post-transcriptional level and are key modulators in neurodegenerative diseases.Overexpressed miRNAs play an important role in amyotrophic lateral sclerosis(ALS);however,the pathogenic mechanisms of deregulated miRNAS are still unclear.Methods:We aimed to assess the dysfunction of RNAS or miRNAs in fALS(SOD1 mutations).We compared the RNA-seq of subcellular fractions in NSC-34 WT(hSOD1)and MT(hSOD1(G93A))cells to find altered RNAs or miRNAs.We identified that Hif1a and Mef2c were upregulated,and Mctp1 and Rarb were downregulated in the cytoplasm of NSC-34 MT cells.Results:SOD1 mutations decreased the level of miR-18b-5p.Induced Hif1a which is the target for miR-18b increased Mef2c expression as a transcription factor.Mef2c upregulated miR-206 as a transcription factor.Inhibition of Mctp1 and Rarb,which are targets of miR-206,induced intracellular Ca^2+ levels and reduced cell differentiation,respectively.The miR-18b-5p pathway was also observed in G93A Tg mice,fALS(G86S)patient,and iPSC-derived motor neurons from fALS(G17S)patient.Conclusions:Our data indicate that SOD1 mutation decreases miR-18b-5p,which sequentially regulates Hif1a,Mef2c,miR-206,Mctp1 and Rarb in fALS-linked SOD1 mutation.These results provide new insights into the downregulation of miR-18b-5p-dependent pathogenic mechanisms of ALS.
