骨关节炎是一种常见的慢性进行性骨关节病，严重影响国民健康。目前对骨关节炎的病理分子机制还不清楚，没有行之有效的预防和治疗方案。骨关节炎主要表现为关节软骨的变性，关节软骨细胞出现肥大和凋亡等病理现象。已知表观遗传的改变与骨关节炎有密切关系。我们前期研究发现，组蛋白H3K36甲基转移酶NSD1在中胚层间质干细胞或者软骨细胞中条件性敲除，导致小鼠关节软骨处蛋白聚糖下降，关节缘骨质增厚，肥大细胞数目增加，表现出骨关节炎类似表型。本项目拟利用组织化学和μCT分析等技术手段，进一步分析Nsd1基因对软骨发育与常见骨关节炎模型的影响。同时利用生物化学和分子生物学的方法，结合离体软骨细胞培养，鉴定NSD1以及组蛋白H3K36甲基化对下游基因转录的影响，研究NSD1在关节软骨细胞分化、成熟以及骨关节炎发生、进展中的作用及其分子机制。本项目的实施将有助于对骨关节炎病理分子机制的理解。

Osteoarthritis is a common chronic progressive bone joint disease, causing high health and economic pressure on society. Because the molecular pathological mechanisms of osteoarthritis remain largely elusive, the effective prevention and treatment programs have yet to be found. Osteoarthritis is mainly manifested as the degeneration of articular cartilage and joint cartilage cells exhibited hypertrophy and apoptosis. Epigenetic alterations are closely related with osteoarthritis. Our previous study found that mesoderm mesenchymal stem cells or chondrocytes specific Nsd1 (an important H3K36 methyltransferase) conditional knockout mice showed osteoarthritis like phenotype with the decrease of articular cartilage proteoglycan, the thicker bone at the edge and the increase of hypertrophic chondrocytes number. We propose to do further cartilage phenotype analysis of Nsd1 conditional knockout mice using histochemical and μCT analysis to understand the effects of NSD1 on articular cartilage development and osteoarthritis model. By the method of biochemistry and molecular biology, combined with in vitro culture of chondrocytes, we will further identify the effects of NSD1 on histone H3K36 methylation and elucidate the role and the molecular mechanism of NSD1 in cell differentiation, maturation of articular cartilage and the progression of osteoarthritis. The project will help to understand the pathological mechanisms of osteoarthritis.