Fibrodysplasia ossificans progressiva(FOP)is a rare genetic disorder characterized by congenital bilateral malformation of the large toe and progressive,extensive,and irreversible heterotopic ossification(HO)of soft t...Fibrodysplasia ossificans progressiva(FOP)is a rare genetic disorder characterized by congenital bilateral malformation of the large toe and progressive,extensive,and irreversible heterotopic ossification(HO)of soft tissues throughout the body,leading to severe disabilities.FOP is caused primarily by mutations in activin A receptor type 1(ACVR1),also known as activin-like kinase 2(ALK2),which encodes a receptor belonging to the bone morphogenetic protein(BMP)type I family.However,the continuous and complex process of HO in FOP is not yet fully understood,which has impeded the development of therapeutic drugs.Despite surgical removal of HO,which often results in recurrence and expansion of ossification,there is currently no definitive drug treatment available to completely prevent,halt,or reverse the progression of HO in FOP.Currently,researchers are intensively studying the pathogenesis of FOP at various stages and developing promising drug candidates,including saracatinib,palovarotene,and rapamycin.This review provides an overview of progress in understanding the mechanism of FOP and the development of therapeutic drugs,with the goal of providing insights for further research and the development of new treatment methods.展开更多
Background: MicroRNAs act as post-transcriptional regulators that repress translation or degrade mRNA transcripts.Each microRNA has many mRNA targets and each mRNA may be targeted by several microRNAs. Skeletal muscle...Background: MicroRNAs act as post-transcriptional regulators that repress translation or degrade mRNA transcripts.Each microRNA has many mRNA targets and each mRNA may be targeted by several microRNAs. Skeletal muscles express a plethora of microRNA genes that regulate muscle development and function by controlling the expression of protein-coding target genes. To expand our understanding of the role of microRNA, specifically btamiR-365-3 p, in muscle biology, we investigated its functions in regulating primary bovine myoblast proliferation and differentiation.Results: Firstly, we found that bta-miR-365-3 p was predominantly expressed in skeletal muscle and heart tissue in Chinese Qinchuan beef cattle. Quantitative PCR and western blotting results showed that overexpression of btamiR-365-3 p significantly reduced the expression levels of cyclin D1(CCND1), cyclin dependent kinase 2(CDK2) and proliferating cell nuclear antigen(PCNA) but stimulated the expression levels of muscle differentiation markers, i.e.,MYOD1, MYOG at both mRNA and protein level. Moreover, downregulation of bta-miR-365-3 p increased the expression of CCND1, CDK2 and PCNA but decreased the expression of MYOD1 and MYOG at both mRNA and protein levels. Furthermore, flow cytometry, EdU proliferation assays and immunostaining results showed that increased levels of bta-miR-365-3 p suppressed cell proliferation but promoted myotube formation, whereas decreased levels of bta-miR-365-3 p resulted in the opposite consequences. Finally, we identified that activin A receptor type I(ACVR1) could be a direct target of bta-miR-365-3 p. It was demonstrated that bta-miR-365-3 p can bind to the 3'UTR of ACVR1 gene to regulate its expression based on dual luciferase gene reporter assays.Consistently, knock-down of ACVR1 was associated with decreased expressions of CDK2, CCND1 and PCNA but increased expression of MYOG and MYOD1 both at mRNA and protein level.Conclusion: Collectively, these data suggested that bta-miR-365-3 p represses proliferation but promotes differentiation of bovine myoblasts through several biological mechanisms involving downregulation of ACVR1.展开更多
基金supported by the National Natural Science Foundation of China(Nos.82370936,81920108012,81970903,and 82270959)the Jilin University Norman Bethune Program(No.2023B28)the Department of Finance of Jilin Province(No.jcsz2023481-37),China.
文摘Fibrodysplasia ossificans progressiva(FOP)is a rare genetic disorder characterized by congenital bilateral malformation of the large toe and progressive,extensive,and irreversible heterotopic ossification(HO)of soft tissues throughout the body,leading to severe disabilities.FOP is caused primarily by mutations in activin A receptor type 1(ACVR1),also known as activin-like kinase 2(ALK2),which encodes a receptor belonging to the bone morphogenetic protein(BMP)type I family.However,the continuous and complex process of HO in FOP is not yet fully understood,which has impeded the development of therapeutic drugs.Despite surgical removal of HO,which often results in recurrence and expansion of ossification,there is currently no definitive drug treatment available to completely prevent,halt,or reverse the progression of HO in FOP.Currently,researchers are intensively studying the pathogenesis of FOP at various stages and developing promising drug candidates,including saracatinib,palovarotene,and rapamycin.This review provides an overview of progress in understanding the mechanism of FOP and the development of therapeutic drugs,with the goal of providing insights for further research and the development of new treatment methods.
基金supported by the National Natural Science Foundation of China (No.31772574)the Program of National Beef Cattle and Yak Industrial Technology System (CARS-37)the scholarship from the China Scholarship Council (CSC),China。
文摘Background: MicroRNAs act as post-transcriptional regulators that repress translation or degrade mRNA transcripts.Each microRNA has many mRNA targets and each mRNA may be targeted by several microRNAs. Skeletal muscles express a plethora of microRNA genes that regulate muscle development and function by controlling the expression of protein-coding target genes. To expand our understanding of the role of microRNA, specifically btamiR-365-3 p, in muscle biology, we investigated its functions in regulating primary bovine myoblast proliferation and differentiation.Results: Firstly, we found that bta-miR-365-3 p was predominantly expressed in skeletal muscle and heart tissue in Chinese Qinchuan beef cattle. Quantitative PCR and western blotting results showed that overexpression of btamiR-365-3 p significantly reduced the expression levels of cyclin D1(CCND1), cyclin dependent kinase 2(CDK2) and proliferating cell nuclear antigen(PCNA) but stimulated the expression levels of muscle differentiation markers, i.e.,MYOD1, MYOG at both mRNA and protein level. Moreover, downregulation of bta-miR-365-3 p increased the expression of CCND1, CDK2 and PCNA but decreased the expression of MYOD1 and MYOG at both mRNA and protein levels. Furthermore, flow cytometry, EdU proliferation assays and immunostaining results showed that increased levels of bta-miR-365-3 p suppressed cell proliferation but promoted myotube formation, whereas decreased levels of bta-miR-365-3 p resulted in the opposite consequences. Finally, we identified that activin A receptor type I(ACVR1) could be a direct target of bta-miR-365-3 p. It was demonstrated that bta-miR-365-3 p can bind to the 3'UTR of ACVR1 gene to regulate its expression based on dual luciferase gene reporter assays.Consistently, knock-down of ACVR1 was associated with decreased expressions of CDK2, CCND1 and PCNA but increased expression of MYOG and MYOD1 both at mRNA and protein level.Conclusion: Collectively, these data suggested that bta-miR-365-3 p represses proliferation but promotes differentiation of bovine myoblasts through several biological mechanisms involving downregulation of ACVR1.
