软骨细胞去分化和过度凋亡是大骨节病重要的病理损害，机制不明，缺乏有效干预方法。近期研究表明ADAM12可激活IGF信号通路，在软骨生长发育、软骨细胞分化和凋亡、骨关节炎软骨损伤中发挥重要作用。预实验发现大骨节病软骨ADAM12和IGF信号通路的表达和功能异常。本项目采用流行病学调查、人群筛检、RNA干扰、细胞和动物实验技术研究：1）ADAM12介导的IGF信号通路调控在大骨节病软骨细胞去分化和过度凋亡中的作用及干预效果；2）ADAM12介导的IGF信号通路调控在T-2毒素中毒、低硒诱导软骨细胞损伤中的作用及干预效果；3）外周血、尿液中ADAM12的变化与大骨节病发生发展的关系。验证“环境危险因素-ADAM12介导的IGF信号通路调控异常—软骨细胞去分化、过度凋亡”的大骨节病软骨损伤机制新假说，预期可推进深入认识大骨节病分子发病机制，为防治方法研究提供科学依据，具有重要科学意义和应用价值。

Chondrocyte dedifferentiation and excessive apoptosis are the important pathologic damage of Kashin-Beck disease (KBD) without effective intervention measures. The biological mechanism of KBD chondrocyte dedifferentiation and excessive apoptosis remains unclear now. The latest studies demonstrated that ADAM12 could activate insulin-like growth factor (IGF) signaling pathway, and play important roles in the growth and development of cartilage, regulation of chondrocyte differentiation and apoptosis, and cartilage damage of osteoarthritis. Our pre-experiments observed abnormal expression and biological function of ADAM12 and IGF signaling pathway in KBD articular cartilage. Using epidemiologic investigation, population screening test, RNA interference, cell and animal experiment technologies, this project will investigate: 1) the role and intervention effect of ADAM12 mediated regulation of IGF signaling pathway in the chondrocyte dedifferentiation and excessive apoptosis of KBD; 2) the role and intervention effect of ADAM12 mediated regulation of IGF signaling pathway in the cartilage damage caused by T-2 toxin and low selenium; 3) the relationships between KBD and ADAM12 levels in serum and urine. This project proposes and explores the novel hypothesis of KBD cartilage damage, that is "KBD environmental risk factors - dysfunction of ADAM12 mediated regulation of IGF signaling pathway - chondrocyte dedifferentiation and excessive apoptosis". The study results will promote deeply understanding the molecular mechanism of KBD cartilage damage, and provide scientific basis for the studies of preventing and treating measures of KBD, which have important scientific significance and application values.