Osteoporosis caused by aging is characterized by reduced bone mass and accumulated adipocytes in the bone marrow cavity. How the balance between osteoblastogenesis and adipogenesis from bone marrow mesenchymal stem ce...Osteoporosis caused by aging is characterized by reduced bone mass and accumulated adipocytes in the bone marrow cavity. How the balance between osteoblastogenesis and adipogenesis from bone marrow mesenchymal stem cells(BMSCs) is lost upon aging is still unclear. Here, we found that the RNA-binding protein Musashi2(Msi2) regulates BMSC lineage commitment. Msi2 is commonly enriched in stem cells and tumor cells. We found that its expression was downregulated during adipogenic differentiation and upregulated during osteogenic differentiation of BMSCs. Msi2 knockout mice exhibited decreased bone mass with substantial accumulation of marrow adipocytes, similar to aging-induced osteoporosis. Depletion of Msi2 in BMSCs led to increased adipocyte commitment. Transcriptional profiling analysis revealed that Msi2 deficiency led to increased PPARγ signaling.RNA-interacting protein immunoprecipitation assays demonstrated that Msi2 could inhibit the translation of the key adipogenic factor Cebpα, thereby inhibiting PPAR signaling. Furthermore, the expression of Msi2 decreased significantly during the aging process of mice, indicating that decreased Msi2 function during aging contributes to abnormal accumulation of adipocytes in bone marrow and osteoporosis. Thus, our results provide a putative biochemical mechanism for aging-related osteoporosis, suggesting that modulating Msi2 function may benefit the treatment of bone aging.展开更多
A distinct population of skeletal stem/progenitor cells(SSPCs)has been identified that is indispensable for the maintenance and remodeling of the adult skeleton.However,the cell types that are responsible for age-rela...A distinct population of skeletal stem/progenitor cells(SSPCs)has been identified that is indispensable for the maintenance and remodeling of the adult skeleton.However,the cell types that are responsible for age-related bone loss and the characteristic changes in these cells during aging remain to be determined.Here,we established models of premature aging by conditional depletion of Zmpste24(Z24)in mice and found that Prx1-dependent Z24 deletion,but not Osx-dependent Z24 deletion,caused significant bone loss.However,Acan-associated Z24 depletion caused only trabecular bone loss.Single-cell RNA sequencing(sc RNA-seq)revealed that two populations of SSPCs,one that differentiates into trabecular bone cells and another that differentiates into cortical bone cells,were significantly decreased in Prx1-Cre;Z24^(f/f)mice.Both premature SSPC populations exhibited apoptotic signaling pathway activation and decreased mechanosensation.Physical exercise reversed the effects of Z24depletion on cellular apoptosis,extracellular matrix expression and bone mass.This study identified two populations of SSPCs that are responsible for premature aging-related bone loss.The impairment of mechanosensation in Z24-deficient SSPCs provides new insight into how physical exercise can be used to prevent bone aging.展开更多
Craniosynostosis is a rare disease in which one or more of the cranial sutures in an infant skull prematurely fuses by turning into bone,with a prevalence of 1 in 2,000—2,500 individuals from reports in Western count...Craniosynostosis is a rare disease in which one or more of the cranial sutures in an infant skull prematurely fuses by turning into bone,with a prevalence of 1 in 2,000—2,500 individuals from reports in Western countries(Wilkie et al.,2017).It may restrict the growth of the brain,leading to some degree of morphological and functional abnormalities,and may affect the neurocognitive function of infants(Lattanzi et al.,2017).Genetic variants underlying craniosynostosis have been identified in cohort studies in Western populations.展开更多
基金supported by the National Natural Science Foundation of China(NSFC)[81672119 and 81725010 to W.Z.]W Z is a scholar of‘the National Science Fund for Distinguished Young Scholars’(NSFC)[81725010]+4 种基金the Strategic Priority Research Program of the Chinese Academy of Science(XDA16020400 to P.H.)Ministry of Science and Technology of China(2017YFA0102700 to P.H.)National Natural Science Foundation of China(32170804 to PH)P.H.the fellowship of China Postdoctoral Science Foundation(2021TQ0207,2021M702184 to J.S.)the‘Basic research project of Shanghai Sixth People’s Hospital’(ynqn202102 to J.S.)。
文摘Osteoporosis caused by aging is characterized by reduced bone mass and accumulated adipocytes in the bone marrow cavity. How the balance between osteoblastogenesis and adipogenesis from bone marrow mesenchymal stem cells(BMSCs) is lost upon aging is still unclear. Here, we found that the RNA-binding protein Musashi2(Msi2) regulates BMSC lineage commitment. Msi2 is commonly enriched in stem cells and tumor cells. We found that its expression was downregulated during adipogenic differentiation and upregulated during osteogenic differentiation of BMSCs. Msi2 knockout mice exhibited decreased bone mass with substantial accumulation of marrow adipocytes, similar to aging-induced osteoporosis. Depletion of Msi2 in BMSCs led to increased adipocyte commitment. Transcriptional profiling analysis revealed that Msi2 deficiency led to increased PPARγ signaling.RNA-interacting protein immunoprecipitation assays demonstrated that Msi2 could inhibit the translation of the key adipogenic factor Cebpα, thereby inhibiting PPAR signaling. Furthermore, the expression of Msi2 decreased significantly during the aging process of mice, indicating that decreased Msi2 function during aging contributes to abnormal accumulation of adipocytes in bone marrow and osteoporosis. Thus, our results provide a putative biochemical mechanism for aging-related osteoporosis, suggesting that modulating Msi2 function may benefit the treatment of bone aging.
基金supported by the National Natural Science Foundation of China (NSFC) (82230082,81991512 to W.Z.,82202742 to J.S.,82070108 to R.Y.)the National Key Research and Development Program of China (2022YFA0806600 to W.Z.,2022YFA1103200 to R.Y.)CAS Project for Young Scientists in Basic Research (YSBR077 to W.Z.)。
文摘A distinct population of skeletal stem/progenitor cells(SSPCs)has been identified that is indispensable for the maintenance and remodeling of the adult skeleton.However,the cell types that are responsible for age-related bone loss and the characteristic changes in these cells during aging remain to be determined.Here,we established models of premature aging by conditional depletion of Zmpste24(Z24)in mice and found that Prx1-dependent Z24 deletion,but not Osx-dependent Z24 deletion,caused significant bone loss.However,Acan-associated Z24 depletion caused only trabecular bone loss.Single-cell RNA sequencing(sc RNA-seq)revealed that two populations of SSPCs,one that differentiates into trabecular bone cells and another that differentiates into cortical bone cells,were significantly decreased in Prx1-Cre;Z24^(f/f)mice.Both premature SSPC populations exhibited apoptotic signaling pathway activation and decreased mechanosensation.Physical exercise reversed the effects of Z24depletion on cellular apoptosis,extracellular matrix expression and bone mass.This study identified two populations of SSPCs that are responsible for premature aging-related bone loss.The impairment of mechanosensation in Z24-deficient SSPCs provides new insight into how physical exercise can be used to prevent bone aging.
基金supported by the foundation of Shanghai municipal commission of Health and Family Planning(20174Y0088)the Shanghai Municipal Science and Technology Major Project(2017SHZDZX01)+1 种基金the CAS Interdisciplinary Innovation Team Projectthe NIHR Oxford Biomedical Research Centre Programme。
文摘Craniosynostosis is a rare disease in which one or more of the cranial sutures in an infant skull prematurely fuses by turning into bone,with a prevalence of 1 in 2,000—2,500 individuals from reports in Western countries(Wilkie et al.,2017).It may restrict the growth of the brain,leading to some degree of morphological and functional abnormalities,and may affect the neurocognitive function of infants(Lattanzi et al.,2017).Genetic variants underlying craniosynostosis have been identified in cohort studies in Western populations.
