Kindlin-2调节成骨间充质干细胞分化和骨代谢的作用及机制

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.

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是一种粘着斑蛋白分子负责整合素的激活。我们前期的研究显示，在小鼠间充质干细胞中敲除Kindlin-2的表达造成软骨内成骨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失，作为本项目的研究基础，我们首次证明了Kindlin-2调节骨骼发育的重要作用。本项目的主要研究内容包括：进一步研究Kindlin-2在骨骼发育与稳态中的作用和机制: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。本项目所资助的相关研究成果发表或已接收文章46篇，其中影响因子大于10.0的有23篇。带有该项目标注的通讯（含共同）作者文章18篇，其中影响因子大于10.0的有10篇。文章发表在Nature Aging 、Nat Communications(3篇)、Signal Transduct Target Ther （STTT）、Autophagy、Bone Research(7篇)、Diabetes、J Am Soc Nephrol（JASN）、JCI Insight(2篇)、Nature Metabolism、Blood (2篇)、Ann Rheum Dis (3篇)、Developmental Cell、J Clin Invest、Cell Death Differ、J Cell Biol、Cell Rep、J Bone Miner Res等国际高水平杂志上。培养一名国自然优秀青年基金获得者。举办了2019年国际华人骨科研究大会（ICMRC-2019）及四次“国际华人骨科高峰论坛”。本课题负责人于2019年成功入选ASBMR会士。本项目顺利完成研究目标，加深了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了新的分子理论基础。

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