Genetic studies have revealed a critical role of Distal-homeobox (Dlx) genes in bone formation,and our previous study showed that Dlx2 overexpressing in neural crest cells leads to profound abnormalities of the cranio...Genetic studies have revealed a critical role of Distal-homeobox (Dlx) genes in bone formation,and our previous study showed that Dlx2 overexpressing in neural crest cells leads to profound abnormalities of the craniofacial tissues.The aim of this study was to investigate the role and the underlying molecular mechanisms of Dlx2 in osteogenic differentiation of mouse bone marrow stromal cells (BMSCs) and pre-osteoblast MC3T3-E1 cells.Initially,we observed upregulation of Dlx2 during the early osteogenesis in BMSCs and MC3T3-E1 cells.Moreover,Dlx2 overexpression enhanced alkaline phosphatase (ALP) activity and extracellular matrix mineralization in BMSCs and MC3T3-E1 cell line.In addition,micro-CT of implanted tissues in nude mice confirmed that Dlx2 overexpression in BMSCs promoted bone formation in vivo.Unexpectedly,Dlx2 overexpression had little impact on the expression level of the pivotal osteogenic transcription factors Runx2,Dlx5,Msx2,and Osterix,but led to upregulation of Alp and Osteocalcin (OCN),both of which play critical roles in promoting osteoblast maturation.Importantly,luciferase analysis showed that Dlx2 overexpression stimulated both OCN and Alp promoter activity.Through chromatin-immunoprecipitation assay and site-directed mutagenesis analysis,we provide molecular evidence that Dlx2 transactivates OCN and Alp expression by directly binding to the Dlx2-response cis-acting elements in the promoter of the two genes.Based on these findings,we demonstrate that Dlx2 overexpression enhances osteogenic differentiation in vitro and accelerates bone formation in vivo via direct upregulation of the OCN and Alp gene,suggesting that Dlx2 plays a crucial role in osteogenic differentiation and bone formation.展开更多
背景非酒精性脂肪性肝病(NAFLD)的发病率逐年上升,已成为重大公共卫生问题之一。血清骨钙素(OCN)是骨形成的标志,可能增加NAFLD的风险。目的本研究进行Meta分析,以定量评估影像学或活检证实的NAFLD与OCN水平之间的关系。方法计算机检索M...背景非酒精性脂肪性肝病(NAFLD)的发病率逐年上升,已成为重大公共卫生问题之一。血清骨钙素(OCN)是骨形成的标志,可能增加NAFLD的风险。目的本研究进行Meta分析,以定量评估影像学或活检证实的NAFLD与OCN水平之间的关系。方法计算机检索Medline、Embase、Web of Science、Cochrane Library、PROSPERO以及中国知网(CNKI)、万方数据知识服务平台和中维普网(VIP)中有关血清OCN与NAFLD的病例对照研究、横断面研究和队列研究。由2名研究人员筛选文献、提取数据并进行质量评价。采用Stata 16.0软件进行Meta分析。结果共纳入13篇文献,包含11772例参与者。Meta分析结果显示,NAFLD患者血清OCN水平低于非NAFLD者(SMD=-0.73,95%CI=-1.20~-0.27,P<0.05);血清OCN最低四分位数NFALD发生率高于OCN最高四分位数(OR=2.19,95%CI=1.15~4.17,P<0.05)。亚组分析结果显示,是否合并基础疾病、研究质量、研究设计不是异质性的来源。敏感性分析结果表明,删除1项研究后Meta荟萃分析的结果没有显著变化,表明结果稳定可靠。Egger's检验未发现统计学发表偏倚(P=0.519)。结论研究结果表明,血清OCN水平与NAFLD发生风险增加呈负相关。展开更多
基金supported by grant (81771036) from National Natural Science Foundation of China (to S.G.S.)grant (81741028) from National Natural Science Foundation of China (to J.D.)grant (17410710500) Shanghai International Scientific and Technological Cooperation Projects Laser Micromachine and Vascularization of TCP/PCL Scaffolds (to W.Z.)
文摘Genetic studies have revealed a critical role of Distal-homeobox (Dlx) genes in bone formation,and our previous study showed that Dlx2 overexpressing in neural crest cells leads to profound abnormalities of the craniofacial tissues.The aim of this study was to investigate the role and the underlying molecular mechanisms of Dlx2 in osteogenic differentiation of mouse bone marrow stromal cells (BMSCs) and pre-osteoblast MC3T3-E1 cells.Initially,we observed upregulation of Dlx2 during the early osteogenesis in BMSCs and MC3T3-E1 cells.Moreover,Dlx2 overexpression enhanced alkaline phosphatase (ALP) activity and extracellular matrix mineralization in BMSCs and MC3T3-E1 cell line.In addition,micro-CT of implanted tissues in nude mice confirmed that Dlx2 overexpression in BMSCs promoted bone formation in vivo.Unexpectedly,Dlx2 overexpression had little impact on the expression level of the pivotal osteogenic transcription factors Runx2,Dlx5,Msx2,and Osterix,but led to upregulation of Alp and Osteocalcin (OCN),both of which play critical roles in promoting osteoblast maturation.Importantly,luciferase analysis showed that Dlx2 overexpression stimulated both OCN and Alp promoter activity.Through chromatin-immunoprecipitation assay and site-directed mutagenesis analysis,we provide molecular evidence that Dlx2 transactivates OCN and Alp expression by directly binding to the Dlx2-response cis-acting elements in the promoter of the two genes.Based on these findings,we demonstrate that Dlx2 overexpression enhances osteogenic differentiation in vitro and accelerates bone formation in vivo via direct upregulation of the OCN and Alp gene,suggesting that Dlx2 plays a crucial role in osteogenic differentiation and bone formation.
文摘背景非酒精性脂肪性肝病(NAFLD)的发病率逐年上升,已成为重大公共卫生问题之一。血清骨钙素(OCN)是骨形成的标志,可能增加NAFLD的风险。目的本研究进行Meta分析,以定量评估影像学或活检证实的NAFLD与OCN水平之间的关系。方法计算机检索Medline、Embase、Web of Science、Cochrane Library、PROSPERO以及中国知网(CNKI)、万方数据知识服务平台和中维普网(VIP)中有关血清OCN与NAFLD的病例对照研究、横断面研究和队列研究。由2名研究人员筛选文献、提取数据并进行质量评价。采用Stata 16.0软件进行Meta分析。结果共纳入13篇文献,包含11772例参与者。Meta分析结果显示,NAFLD患者血清OCN水平低于非NAFLD者(SMD=-0.73,95%CI=-1.20~-0.27,P<0.05);血清OCN最低四分位数NFALD发生率高于OCN最高四分位数(OR=2.19,95%CI=1.15~4.17,P<0.05)。亚组分析结果显示,是否合并基础疾病、研究质量、研究设计不是异质性的来源。敏感性分析结果表明,删除1项研究后Meta荟萃分析的结果没有显著变化,表明结果稳定可靠。Egger's检验未发现统计学发表偏倚(P=0.519)。结论研究结果表明,血清OCN水平与NAFLD发生风险增加呈负相关。
