脊柱骨骺干骺端发育不良是一组以身材矮小、先天性关节活动异常及早发性骨关节炎等为主要临床特征的遗传性骨病，严重影响青少年健康。我们前期临床诊断一个常显遗传方式的脊柱骨骺干骺端发育不良大家系，令人兴奋的是，我们通过进一步研究明确CTGF是该疾病的新致病基因。已发现CTGF是软骨内成骨过程关键因子，并且参与关节软骨稳态维持与损伤修复，但此前该基因突变导致人类疾病未见报道。因此，本项目拟在我们已构建成功的CTGF基因R21P点突变敲入小鼠模型基础上，建立骨关节炎小鼠模型，通过体内外实验明确CTGF在骨软骨发育及关节软骨稳态维持，尤其在骨关节炎发生发展中的关键作用，并探讨CTGF在骨关节炎干预中的潜在价值。本项目有望阐明CTGF基因突变致家族性脊柱骨骺干骺端发育不良的发病机制，并明确CTGF对骨关节炎的作用，为其治疗药物研发提供关键靶点。

Spondyloepimetaphyseal dysplasia (SEMD) is the collective term for a clinically and genetically heterogeneous group of inherited human skeletal disorders, seriously affecting the health among adolescents. The clinical phenotypes of affected subjects are usually short-stature, abnormal joint motion, and early-onset osteoarthritis (OA). We previously collected a pedigree of SEMD with autosomal-dominant pattern of inheritance. Interestingly, further studies revealed that CTGF was a new disease-causing gene in the familial SEMD. Previous studies have shown that CTGF is a critical regulator implicated in the process of endochondral ossification, indicating the key role of CTGF in skeleton development. Moreover, emerging evidences suggest that CTGF is a promising regeneration factor that plays an important role in articular cartilage homeostasis. However, no human mendelian disorders were found to be linked to germline mutations in CTGF previously. In this study, we intend to use CTGF mutation knock-in mice model as well as OA mice model to clarify the role of CTGF in bone formation and in homeostasis of articular cartilage, especially its role in the development of OA, and to explore the potential application value of CTGF in OA treatment. This study is expected to elucidate the molecular mechanism of CTGF gene mutation in pathogenesis of SEMD, and to gain understanding of pathogenesis of OA, as well providing new insight for the development of therapy for OA.