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
The decreased osteoblast differentiation associated with reduced bone formation is one main cause of microgravityinduced bone loss.Our previous studies have demonstrated that microtubule actin crosslinking factor 1(MA...The decreased osteoblast differentiation associated with reduced bone formation is one main cause of microgravityinduced bone loss.Our previous studies have demonstrated that microtubule actin crosslinking factor 1(MACF1)is downregulated in association with the decreased osteoblast differentiation and bone formation under simulated microgravity conditions.These findings suggest that MACF1 is sensitive to mechanical condition and may be critical for osteoblast differentiation and bone formation.To verify this hypothesis,current study investigates the role and mechanism of MACF1 in regulatingosteoblast differentiation by adopting MACF1 knockdown(MACF1-KD)osteoblasts.The results showed that MACF1 knockdown suppressed mineralized nodules formation,alkaline phosphatase(ALP)activity,osteogenic gene expression andβ-catenin signaling transduction.Moreover,we used RNA sequencing(RNA-seq)and chromatin immunoprecipitation sequencing(ChIP-seq)to investigate further mechanism.Interestingly,we found that MACF1 sequesterd repressors of osteoblast differentiation in cytoplasm.In conclusion,MACF1 is sensitive to mechanical condition and plays key role in activatingβ-catenin signaling transduction and sequestering repressors of osteoblast differentiation,which further promotes osteoblast differentiation.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supported by the National Natural Science Foundation of China ( 81772017,31570940)Young Talent Fund of University Association for Science and Technology in Shaanxi,China ( 20170401)Supported by Natural Science Basic Research Plan in Shaanxi Province of China ( 2018JM3040)
文摘The decreased osteoblast differentiation associated with reduced bone formation is one main cause of microgravityinduced bone loss.Our previous studies have demonstrated that microtubule actin crosslinking factor 1(MACF1)is downregulated in association with the decreased osteoblast differentiation and bone formation under simulated microgravity conditions.These findings suggest that MACF1 is sensitive to mechanical condition and may be critical for osteoblast differentiation and bone formation.To verify this hypothesis,current study investigates the role and mechanism of MACF1 in regulatingosteoblast differentiation by adopting MACF1 knockdown(MACF1-KD)osteoblasts.The results showed that MACF1 knockdown suppressed mineralized nodules formation,alkaline phosphatase(ALP)activity,osteogenic gene expression andβ-catenin signaling transduction.Moreover,we used RNA sequencing(RNA-seq)and chromatin immunoprecipitation sequencing(ChIP-seq)to investigate further mechanism.Interestingly,we found that MACF1 sequesterd repressors of osteoblast differentiation in cytoplasm.In conclusion,MACF1 is sensitive to mechanical condition and plays key role in activatingβ-catenin signaling transduction and sequestering repressors of osteoblast differentiation,which further promotes osteoblast differentiation.
