Mechanical stimuli play an essential role in maintaining bone remodeling and skeletal integrity.Meanwhile,bone can respond to the changes of mechanical condition to adjust its mass and architecture.Clinical studies di...Mechanical stimuli play an essential role in maintaining bone remodeling and skeletal integrity.Meanwhile,bone can respond to the changes of mechanical condition to adjust its mass and architecture.Clinical studies discover that bedridden patients showed osteoporotic T-scores and low bone mineral density,and long-term immobilized patients presented reduced markers of bone formation.However,as bone formation mediated by osteoblast differentiation is a complex process,the underlying molecular mechanism of mechanical stimuli regulating bone formation is still unclear.Recent evidences show that microRNAs(miRNAs)are involved in mechanical stimuli regulating bone formation or osteoblast differentiation.Nevertheless,no direct evidence identifies mechanoresponsive miRNA in both human and animal bones,and clarifies its mechanoresponsive role under different mechanical conditions(e.g.mechanical unloading,reloading,loading).In the current study,we screened for differentially expressed miRNAs in bone specimens of bedridden patients with fractures,then identified that the expression of miR-138-5p,but not the other miRNAs,altered withbedridden time and was negatively correlated with the expression of the bone formation marker genes Alp(alkaline phosphatase).Moreover,miR-138-5p was up-regulated with reduced bone formation during unloading and down-regulated with increased bone formation during reloading in hind4imb unloaded mice.In addition,miR-138-5p was verified to be responsive to different mechanical unloading condition and cyclic mechanical stretch condition in primary osteogenic cells,respectively.Further in vitro data suggested that mechanoresponsive miR-138-5p directly targeted microtubule actin crosslinking factor 1(MACF1)to inhibit osteoblast differentiation.In vivo,we constructed an osteoblastic miR-138-5p transgenic mice model(TG138)with the Runx2promoter,and found that overexpression miR-138-5p supressed bone formation.Moreover,osteoblast-targeted inhibition of miR-138-5p sensitized bone anabolic response to mechanical loading in TG138 mice.Predominantly,the osteoblast-targeted inhibition of miR-138-5p could counteract bone formation reduction induced by hind limb unloading.Taken together,the mechanoresponsive miR-138-5p inhibited bone anabolic response for developing a novel bone anabolic sensitization strategy.展开更多
Tooth mineralization is a ubiquitous and tightly regulated process involving complicated interactions between dental epithelium and mesenchyme.Key molecules in tooth mineralization remain poorly identified.Microtubule...Tooth mineralization is a ubiquitous and tightly regulated process involving complicated interactions between dental epithelium and mesenchyme.Key molecules in tooth mineralization remain poorly identified.Microtubule actin cross-linking factor 1(MACF1)is a spectraplakin protein that plays pivotal roles in the brain,muscle,lung,and bone developmental process.^(1-3) To study the specific functions of MACF1 in bone formation,we established Macf1 conditional knockout mice using the Cre-LoxP system driven by Osxterix promoter(Osx-Cre;Macf1^(f/f)).^(2) Not surprisingly,Osx-Cre;Macf1^(f/f) mice displayed the phenotypes of delayed ossification and decreased bone mass.Moreover,the OsxCre;Macf1^(f/f) mice unexpectedly showed a white and opaque appearance of incisors,contrary to the normal yellowbrown and transparent incisors.Since Osxterix is expressed in dental mesenchyme during tooth development,the abnormal tooth appearance might imply a new function of MACF1 in odontoblasts,or even ameloblasts.Therefore,the present study aimed to investigate the role of MACF1 during tooth development.展开更多
Lung metastasis is the primary cause of death in osteosarcoma(OS)patients.1 A better understanding of the molecular mechanisms underlying OS tumorigenesis and metastasis is urgently needed to identify therapeutic targ...Lung metastasis is the primary cause of death in osteosarcoma(OS)patients.1 A better understanding of the molecular mechanisms underlying OS tumorigenesis and metastasis is urgently needed to identify therapeutic targets.Microtubule actin crosslinking factor 1(MACF1),which belongs to the spectraplakin family of cytoskeletal crosslinking proteins,2 is critical for cell migration and polarization due to its regulation of the cytoskeleton.Recently,MACF1 was indicated to be involved in the metastatic invasion of some human cancers,3 but the function of MACF1 in OS is still unclear.展开更多
基金supported by the National Natural Science Foundation of China ( 31570940,81772017)
文摘Mechanical stimuli play an essential role in maintaining bone remodeling and skeletal integrity.Meanwhile,bone can respond to the changes of mechanical condition to adjust its mass and architecture.Clinical studies discover that bedridden patients showed osteoporotic T-scores and low bone mineral density,and long-term immobilized patients presented reduced markers of bone formation.However,as bone formation mediated by osteoblast differentiation is a complex process,the underlying molecular mechanism of mechanical stimuli regulating bone formation is still unclear.Recent evidences show that microRNAs(miRNAs)are involved in mechanical stimuli regulating bone formation or osteoblast differentiation.Nevertheless,no direct evidence identifies mechanoresponsive miRNA in both human and animal bones,and clarifies its mechanoresponsive role under different mechanical conditions(e.g.mechanical unloading,reloading,loading).In the current study,we screened for differentially expressed miRNAs in bone specimens of bedridden patients with fractures,then identified that the expression of miR-138-5p,but not the other miRNAs,altered withbedridden time and was negatively correlated with the expression of the bone formation marker genes Alp(alkaline phosphatase).Moreover,miR-138-5p was up-regulated with reduced bone formation during unloading and down-regulated with increased bone formation during reloading in hind4imb unloaded mice.In addition,miR-138-5p was verified to be responsive to different mechanical unloading condition and cyclic mechanical stretch condition in primary osteogenic cells,respectively.Further in vitro data suggested that mechanoresponsive miR-138-5p directly targeted microtubule actin crosslinking factor 1(MACF1)to inhibit osteoblast differentiation.In vivo,we constructed an osteoblastic miR-138-5p transgenic mice model(TG138)with the Runx2promoter,and found that overexpression miR-138-5p supressed bone formation.Moreover,osteoblast-targeted inhibition of miR-138-5p sensitized bone anabolic response to mechanical loading in TG138 mice.Predominantly,the osteoblast-targeted inhibition of miR-138-5p could counteract bone formation reduction induced by hind limb unloading.Taken together,the mechanoresponsive miR-138-5p inhibited bone anabolic response for developing a novel bone anabolic sensitization strategy.
基金the National Natural Science Foundation of China(No.30970706,81700784,81974145)the Fundamental Research Funds for the Central Universities(China)(No.D5000210746)+2 种基金the Key Research and Development Project of Shaanxi Province(China)(No.2021SF-293,2021SF-242)the Talent Introduction Project of Sichuan University of Science and Engineering(No.2022RC01)the Guangdong Basic and Applied Basic Research Foundation(China)(No.2023A1515030047).
文摘Tooth mineralization is a ubiquitous and tightly regulated process involving complicated interactions between dental epithelium and mesenchyme.Key molecules in tooth mineralization remain poorly identified.Microtubule actin cross-linking factor 1(MACF1)is a spectraplakin protein that plays pivotal roles in the brain,muscle,lung,and bone developmental process.^(1-3) To study the specific functions of MACF1 in bone formation,we established Macf1 conditional knockout mice using the Cre-LoxP system driven by Osxterix promoter(Osx-Cre;Macf1^(f/f)).^(2) Not surprisingly,Osx-Cre;Macf1^(f/f) mice displayed the phenotypes of delayed ossification and decreased bone mass.Moreover,the OsxCre;Macf1^(f/f) mice unexpectedly showed a white and opaque appearance of incisors,contrary to the normal yellowbrown and transparent incisors.Since Osxterix is expressed in dental mesenchyme during tooth development,the abnormal tooth appearance might imply a new function of MACF1 in odontoblasts,or even ameloblasts.Therefore,the present study aimed to investigate the role of MACF1 during tooth development.
基金supported by the National Natural Science Foundation of China(No.81801871)the Shaanxi Provincial Key R&D Program(No.2021SF-293,2018KWZ-10,2018SF-363)+1 种基金the Special Fund for Technological Innovation of Shaanxi Province(No.2019QYPY-207)the Fundamental Research Funds for the Central Universities(No.3102018zy053,D5000210746).
文摘Lung metastasis is the primary cause of death in osteosarcoma(OS)patients.1 A better understanding of the molecular mechanisms underlying OS tumorigenesis and metastasis is urgently needed to identify therapeutic targets.Microtubule actin crosslinking factor 1(MACF1),which belongs to the spectraplakin family of cytoskeletal crosslinking proteins,2 is critical for cell migration and polarization due to its regulation of the cytoskeleton.Recently,MACF1 was indicated to be involved in the metastatic invasion of some human cancers,3 but the function of MACF1 in OS is still unclear.
