YAP regulates periosteal expansion in early fracture repair.

Periosteal expansion is a key process in the early stages of bone fracture repair. The periosteum is typically quiescent, but upon fracture it expands, periosteal cells proliferate and contribute to the formation of a cartilaginous callus . The early expansion of the periosteum is tightly regulated at the transcriptional level. However, the molecular mechanisms behind periosteal expansion are unknown. Here, we show that Yes-Associated Protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) mediate periosteal expansion and periosteal cell proliferation. Bone fracture results in increased numbers of YAP-expressing periosteal cells. Deletion of YAP from Osterix (Osx) expressing periosteal cells impairs early periosteal expansion. Mechanistically, YAP regulates both cell intrinsic and extrinsic transcriptional programs that allow for periosteal expansion. Specifically, we identified Bmp4 as a cell extrinsic factor regulated by YAP, that rescues the impairment of periosteal expansion upon YAP deletion. Together, these data establish YAP mediated molecular mechanisms that allow for periosteal expansion in the early stages of fracture repair. Overall design: Investigating the role of YAP in modulating the transcriptional landscape in periosteal cells

骨膜扩张（Periosteal expansion）是骨折修复早期的关键进程。骨膜通常处于静息状态，当发生骨折时会发生扩张，骨膜细胞增殖并参与软骨性骨痂的形成。骨膜的早期扩张在转录层面受到严格调控，但目前其背后的分子机制仍未明确。本研究证实，Yes相关蛋白（Yes-Associated Protein, YAP）与PDZ结合基序转录共激活因子（transcriptional co-activator with PDZ-binding motif, TAZ）可介导骨膜扩张及骨膜细胞增殖。骨折会使表达YAP的骨膜细胞数量增多。从表达Osterix（Osx）的骨膜细胞中敲除YAP，会损害早期骨膜扩张过程。从机制层面而言，YAP可调控介导骨膜扩张的细胞内在与细胞外在转录程序。具体而言，本研究鉴定出骨形态发生蛋白4（Bmp4）作为YAP调控的细胞外在因子，其可挽救YAP敲除所导致的骨膜扩张损伤。综上，这些数据确立了YAP介导的骨折修复早期骨膜扩张分子机制。整体实验设计：探究YAP对骨膜细胞转录谱的调控作用。