GDF5介导的发育期颞下颌关节骨关节炎中软骨化骨和生长发育异常的机制研究

项目名称： GDF5介导的发育期颞下颌关节骨关节炎中软骨化骨和生长发育异常的机制研究

项目编号： No.81500877

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 孙志鹏

作者单位： 北京大学

项目金额： 18万元

中文摘要： 申请者的前期临床研究和既往资料表明发育期罹患颞下颌关节骨关节炎（TMJOA）等颞下颌关节疾病易导致髁突及下颌骨发育不良畸形。推测炎症诱发的髁突软骨细胞中软骨化骨异常可能是颌骨发育畸形的重要病理机制。课题组的前期工作中已建立发育期TMJOA导致下颌骨发育畸形的大鼠动物模型，并通过髁突软骨RNA-SEQ筛查得到差异表达的基因26个，其中GDF5在TMJOA关节软骨呈现显著高表达。推测GDF5参与了TMJOA异常软骨内化骨继而导致下颌骨发育受损。本研究拟在前期研究的基础上，进一步验证观察GDF5在TMJOA病理过程中的表达时空变化谱；设计体内体外实验，检测GDF5对软骨细胞终末分化、凋亡的影响， 并进一步验证GDF5与成骨分化的关键因子SOX9，RUNX2和VEGF的相互作用，深入探讨GDF5影响软骨内化骨的分子调控机制。通过特异性阻断GDF5，追踪TMJOA中下颌骨生长发育畸形能否得到纠正.

中文关键词： 颞下颌关节；骨关节炎；下颌骨；软骨化骨；生长分化因子-5

英文摘要： Osteoarthritis frequently leads to skeletal growth impairment. In dentistry, the temporomandibular joint osteoarthritis (TMJOA) frequently leads to hypoplasia deformity of the mandible. The disturbed endochondral ossification in TMJOA accounts for the hypoplasia. But the detailed molecular mechanism is not clear. In our previous work, we have established an animal model using growing rat in which surgically induced TMJOA resulted in mandibular hypoplasia. We used RNA sequencing and real time PCR to find 26 differentially expressed genes in the TMJOA cartilage. GDF5 is known for its regulation of the chondrogenesis and osteogenesis, which had been proved abnormally expressed in TMJOA in our previous study. We aim to further explore its potential role in TMJOA, endochondral ossification and mandible growth. We aim to further explore the interactions between GDF5 and the upstream signal pathways of osteogenesis including VEGF, SOX9 and RUNX2 using real-time PCR and western-blotting in vitro experiments. We aim to focus on the chondro-osseous conjunction and to prove the changed apoptosis of the terminally differentiated mature chondrocytes, abnormal calcification of the cartilage matrix and abnormal angiogenesis. We aim to observe the biological effects of GDF5 on mandible growth intra-articular injection its inhibitor or promoter in both TMJOA and normal joints in vivo experiments. All in all, our work will further elucidate the effects of GDF5 on the endochondral ossification and osteoarthritis.

英文关键词： temporomandibular joint;osteoarthritis;mandible;endochondral ossification;GDF5