成骨细胞特异性转录因子Osterix对骨形成作用的分子机制(英文)

Molecular mechanisms of osteoblast-specific transcription factor Osterix effect on bone formation

骨形成是一个涉及到从间质干细胞向成骨细胞分化的复杂发育过程。成骨细胞定向分化受到一个多步骤的分子通路控制,通过不同的转录因子和信号蛋白调控,包括Indian hedgehog,Runx2,Osterix(Osx),以及Wnt信号通路。Osx是骨形成所必需的成骨细胞特异性转录因子,Osx最早是在间质干细胞被骨形成蛋白-2诱导向成骨细胞分化过程中发现的基因。Osx基因敲除小鼠完全缺乏骨,而软骨是正常的,这为研究骨的形成打开了一个全新的窗口。Osx抑制Wnt信号通路的发现揭示了参与骨形成的一种新的反馈调控机制。骨形成过程中Osx下游的靶目标已经确定一些,包括Satb2、维生素D受体和血管内皮生长因子,以及Dkk1和Sost。骨形成过程一系列信号传导因子的揭示、阐明应当为一些新的特异性合成代谢治疗药物的研究开发提供分子理论基础,以便治疗骨缺失疾病(如骨质疏松症和骨坏死)。本文综述了Osx在骨形成作用分子机制中的最新进展,自Osx发现以来,各种研究证据表明Osx是决定成骨细胞定向的主导因子,继而调控成骨细胞的分化和增殖。

Bone formation is a complex developmental process involving the differentiation of mesenchymal stem cells to osteoblasts.Osteoblast commitment and differentiation are controlled through a multistep molecular pathway regulated by different transcription factors and signaling proteins,including Indian hedgehog,Runx2,Osterix（Osx）,and Wnt pathway.Osx is an osteoblast-specific transcription factor required for bone formation.Osx was first discovered as a bone morphogenetic protein-2 inducible gene in mesenchymal stem cells.Osx knock-out mice lack bone completely,and cartilage is normal.This opens a new window to the whole field of how bone forms.The discovery that Osx inhibits Wnt pathway highlights the potential for novel feedback control mechanisms involved in bone formation.Several downstream targets of Osx during bone formation have been identified,including Satb2,vitamin D receptor and vascular endothelial growth factor as well as Dkk1 and Sost.The delineation of the cascade of events leading to bone formation should provide a molecular basis for the development of new and specific anabolic therapeutic agents for bone deficit conditions,such as osteoporosis and osteonecrosis.This review summarizes the recent advances in understanding the molecular mechanisms of Osx effect on bone formation.Studies since the Osx discovery have provided convincing evidences to demonstrate that Osx is the master gene that controls osteoblast lineage commitment and the subsequent osteoblast differentiation and proliferation.