Kindlin-2是一种局部粘附蛋白，负责整合素的激活。我们首次证明Kindlin-2调节骨骼发育的重要作用。在小鼠MSC中敲除Kindlin-2的表达造成软骨内和膜内成骨受损以及严重的骨骼异常包括短肢和头盖骨完全缺如。我们将进一步研究Kindlin-2的作用和机制：1）阐明控制MSC向成骨细胞系分化的早期信号通路；2）确定Kindlin-2调节软骨膜MSC向骨小梁及骨髓腔迁移的作用和机制；3）确定 Kindlin-2表达在促进骨折愈合中的作用；4）阐明Kindlin-2调节成年骨重塑及介导机械应力调节骨重塑的作用和机制；5）确定衰老、骨质疏松等病理状态对Kindlin-2在骨组织中表达的影响，寻找骨骼病理状态下Kindlin-2表达的调节分子。本项目的顺利完成将加深我们对控制骨骼发育及稳态维持的信号机制的理解，并为发展新的防治人类骨骼疾病如骨质疏松症和骨性关节炎等的策略提供新的分子基础。

Kindlin-2 is a focal adhesion protein that is responsible for integrin activation. We, for the first time, demonstrate that Kindlin-2 plays a critical role in regulation of skeletal development. Mice lacking Kindlin-2 expression in mesenchymal stem cells (MSC) display multiple striking skeletal abnormalities including severe limb shortening and complete loss of skull vault due to impairment of both endochondral and intramembranous bone formation. In this study, we will continue this highly exciting project by using a combination of sophisticated molecular and cellular approaches along with multiple novel mouse models and patient specimen and determine the role and mechanism whereby Kindlin-2 controls skeletal development and homeostasis under physiological and pathological conditions. Specifically, we will: 1) define a new Kindlin-2 signaling pathway that controls MSC differentiation towards the osteoblast lineage; 2) determine the role and mechanism(s) whereby Kindlin-2 regulates the migration of osteogenic MSC from periosteum of long bones to trabecular surfaces and marrow, a critical step of endochondral bone formation; 3) determine the role of Kindlin-2 expression in osteogenic MSC in promotion of fracture healing; 4) determine how the Kindlin-2 signaling controls bone remodeling in adult skeleton and in skeletal response to mechanical loading or unloading in vitro and in vivo; and finally, 5) determine the effects of aging, osteoporosis and estrogen deficiency on expression of Kindlin-2 in skeleton and define novel miRNA molecules that may suppress Kindlin-2 expression under desease state, such as osteoporosis and skeletal aging. Successful completion of this project will advance our understanding of the signaling mechanisms that control skeletal development and homeostasis and provide a molecular basis for development of new strategies for preventing, curing or alleviating human chronic bone diseases, such as osteoporosis and osteoarthritis, both major public problems worldwide.