骨与关节疾病危害严重，但发病机制未阐明。申请者围绕衰老促进信号mTOR与骨与软骨退行性病变的机制开展研究，主持课题10余项(含国家自然科学基金重点项目、“珠江学者”与教育部“新世纪优秀人才”等人才项目)，取得以下成绩：(1) 揭示了mTORC1通过PTHrP协调软骨细胞增与殖分化的机制及其在启动骨关节炎发生中的关键作用(Ann Rheum Dis; Nat Commun)；(2)揭示活性氧调节mTORC1/2、参与骨丢失的分子机制(Cell Death Diff; JBMR; JBC)；(3)发现mTORC1通过Notch通路促进成骨细胞增殖、抑制其分化(PLoS Genet); (4)阐明营养与炎症因子调节mTORC1/2的新机制(Science; J Cell Biol)；近3年发表影响因子大于8的通讯作者论文8篇，第一或通讯作者论文近五年内被Cell、Nature等期刊他引601次。

Bone and joint diseases cause serious health problems, but the pathogenesis of the diseases are not well defined. Funded by a dozen of projects, including the Key Programs of National Natural Science Foundation of China, "Pearl River Scholar" and Education Ministry's "New Century Excellent Talents" Supporting Plan, this applicant investigates the roles and regulatory mechanisms of the mechanistic target of rapamycin (mTOR), a key signaling pathway that senses nutrients and promotes ageing, in the modulation of bone and articular cartilage degeneration, and has made the following achievements: (1) the applicant has uncovered mechanisms through which mTORC1 coordinates chondrocyte proliferation and differentiation via regulation of PTHrP and mTORC1 initiates osteoarthritis via stimulating chondrocyte proliferation and hypertrophy (Ann Rheum Dis; Nat Commun). (2) Uncovered mechanisms through which reactive oxygen species (ROS) regulates mTORC1, and identified the critical roles of ROS in bone loss (Cell Death Diff; JBMR; JBC). (3) The applicant found that mTORC1 prevented preosteoblast differentiation through the Notch signaling pathway (PLoS Genet). (4) Established novel mechanisms that nutrients (amino acids) and inflammatory factors regulate mTORC1/2 (Science; J Cell Biol). As the correspondence author, the applicant has published 8 papers on journals whose impact factor is over 8 since 2013. During the past 5 years, papers publish by the applicant as the first/corresponding author were cited 601 times by papers on journals such as "Cell" and "Nature".