报告题目：Focal adhesion proteins Pinch1/2 regulate skeletal development and homeostasis

报告人：肖国芝 南方科技大学

主持人：罗剑 教授

报告时间：2019年11月14日16:20（周四下午）

报告地点：生命科学学院534小会议室

报告人简介：

肖国芝教授是骨生物学家, 现任南方科技大学生物系教授、致诚书院院长、校实验动物中心主任、ICMRS-南方科技大学联合研究中心主任、ASBMR会士及FIOR会士。美国罗斯大学医学中心骨科系教授、冠名讲座讲习教授。主要研究骨骼发育和骨骼疾病 （骨质疏松，骨关节炎，癌症骨转移及骨折）的相关分子基础。北京大学医学部博士；美国密歇根大学博士后，讲师，研究助理教授；美国匹茨堡大学医学院助理教授、终身副教授；罗斯大学生物化学系的研究主任；历任南方科技大学生物系系主任、校学术委员会委员、校学位委员会委员。主持多个美国国立卫生研究R01基金和美国国防部研究基金；担任科技部973重大项目课题负责人，主持国自然重点课题。相关的研究成果在国际一流学术刊物J Biol Chem、J Clin Invest、J Cell Biol、Nat Commun、Blood、Bone Research、J Am Soc Nephrol.、Autophagy及J Bone Miner Res上发表文章110余篇，引用约9000次；实验室研究成果多次在国际大会上获奖；应邀国际大会及著名大学报告120余次，主办或参与组织国际大会20次，主持国际大会重要专场近30次。担任J Bone Miner Res及 J Biol Chem.等国际学术刊物的编委、45个国际杂志的审稿人。担任美国和意大利研究基金评审专家。担任国家杰出青年基金、优秀青年基金、国际合作重点项目、重点项目及面上项目等基金的会评专家。深圳市高层次引进人才（孔雀学者，A类），北京大学医学部（原北京医科大学）100周年校庆，优秀校友。

报告内容：

Mammalian focal adhesion proteins Pinch1 and Pinch2 regulate integrin activation and cell-ECM adhesion and migration. Here we show that deleting Pinch1 in osteocytes and mature osteoblasts using the 10-kb mouse Dmp1-Cre and Pinch2 globally (double knockout or dKO) results in severe osteopenia throughout life, while ablating either gene does not cause bone loss, suggesting a functional redundancy of both factors in bone. Pinch deletion in osteocytes and mature osteoblasts generates signal(s) that inhibit osteoblast and bone formation. Pinch-deficient osteocytes and conditioned media from dKO bone slices cultures contain abundant sclerostin protein and potently suppresses osteoblast differentiation in primary BMSC and calvarial cultures. Pinch deletion increases adiposity in the bone marrow cavity. Primary dKO BMSC cultures display decreased osteoblastic, but enhanced adipogenic, differentiation capacity. Pinch loss decreases expression of integrin, ILK, and -parvin and increases that of active caspases 3 and 8 in osteocytes. Pinch loss increases osteocyte apoptosis in vitro and in bone. Pinch loss upregulates expression of both Rankl and Opg in the cortical bone and does not increase osteoclast formation and bone resorption. Pinch ablation exacerbates hindlimb unloading-induced bone loss and impairs active ulna loading-stimulated bone formation. Deleting Pinch1/2 in mesenchymal stem cells causes severe chondrodysplasia and low bone mass, while singly mutant does not display those defects. Pinch deletion decreases chondrocyte proliferation, accelerates cell differentiation, and disrupts column formation. Pinch loss drastically reduces Smad2/3 protein expression in the proliferative zone. Finally, ablating Pinch1/2 in chondrocytes causes severe osteopenia with subtle limb shortening. Thus, we establish a critical role of Pinch1/2 in control of skeletogenesis and bone homeostasis.