Osteoprogenitor mobilization for bone development and repair

摘要 由创伤或肿瘤切除引起的大型骨缺损是一个重大的临床挑战，因为它们 如果不介入就无法治愈，目前的植骨疗法有限。组织工程是一种 前景看好的替代方案，但往往受到内源性祖细胞招募或供应不足的限制。不像 大的缺陷，骨折很容易愈合，通过重述骨骼发育的步骤。在骨折修复中， 碎片间应变形式的机械线索对于确定骨骼的路径是必不可少的。 形成，即通过膜内骨化或间接骨形成的直接骨形成。 通过软骨内骨化形成，其中软骨模板首先形成，然后被 骨头。骨祖细胞在骨发育过程中被动员的机制和方式 对于直接修复骨折的机械信号知之甚少。我们观察到了它们的组合作用 机械敏感型转录共激活因子、YAP和转录共激活因子 与PDZ-Motif(TAZ)一起促进骨骼发育和修复。此应用程序的目标是定义 YAP/TAZ在骨发育过程中骨祖细胞动员中的作用 机械载荷介导的骨折修复。实现这一目标将为发展提供新的见解 骨骼疾病，确定可用于促进愈合的途径，并定位我们设计新的 组织工程策略，概括骨发育和自然修复的过程 大块骨缺损的再生。

Abstract Large bone defects caused by traumatic injury or tumor resection pose a significant clinical challenge as they cannot not heal without intervention, and current bone grafting therapies are limited. Tissue engineering is a promising alternative, but is often limited by poor recruitment or supply of endogenous progenitor cells. Unlike large defects, bone fractures heal readily by recapitulating the steps of bone development. In fracture repair, mechanical cues, in the form of interfragmentary strains, are essential to determine the pathway by which bone formation occurs, namely direct bone formation through intramembranous ossification or indirect bone formation through endochondral ossification, in which a cartilage template forms first and is later replaced by bone. The mechanisms by which osteoprogenitor cells are mobilized during bone development and how mechanical cues direct fracture repair are poorly understood. We observed combinatorial roles of the mechanosensitive transcriptional co-activators, Yes-associated protein (YAP) and Transcriptional co-activator with PDZ-motif (TAZ) in promoting both bone development and repair. The goal of this application is to define the mechanistic roles of YAP/TAZ in osteoprogenitor cell mobilization during bone development and mechanical load-mediated fracture repair. Accomplishing this goal will provide new insights into developmental bone diseases, identify pathways that could be exploited to enhance healing, and position us to design new tissue engineering strategies that recapitulate the processes of bone development and natural repair for regeneration of large bone defects.