Viscoelastic Properties of Normal and OA Chondrons

项目摘要/摘要 骨关节炎(OA)是一种高度流行的、致残性的关节退行性疾病，其特征是 关节软骨、软骨下骨和其他关节组织的进行性有害变化。这 该项目将在一组独特的(早发性)家族性骨性关节炎患者中利用外显子组测序的新证据 导致COL6A3高影响突变的病例很可能是骨性关节炎的病因。这个 这种突变增加OA风险的机制尚不清楚，部分原因是有大量的 人群中的遗传变异和生活方式的差异可以影响骨性关节炎的发展。我们 建议开发一种新的体外系统来研究已识别的OA因果变体对 COL6A3基因编辑对兔关节软骨生化和力学特性的影响 多能干细胞与软骨组织工程。VI型胶原蛋白在骨质疏松症 软骨的功能--软骨细胞及其周围的细胞周围基质--已经显示出 调节关节软骨细胞的生物学和生物力学环境。我们将使用 实验和理论相结合的建模方法来确定物理化学的变化 COL6A3突变PCM的性质对软骨细胞间机械相互作用的影响 和软骨分化的IPSCs中的细胞外基质。我们将研究早期的信号事件以及 COL6A3基因敲除或突变对软骨细胞负荷反应的长期影响最后，我们会 检测COL6A3基因敲除或突变对表观遗传控制的改变的影响 软骨细胞对负荷的反应的转录组。对这些机制的详细了解将 对新药理学、再生疗法或物理疗法治疗骨性关节炎的发展提供重要见解。

PROJECT SUMMARY / ABSTRACT Osteoarthritis (OA) is a highly prevalent, disabling degenerative disease of the joints that is characterized by progressive deleterious changes in the articular cartilage, subchondral bone, and other joint tissues. This project will exploit emerging evidence from exome sequencing in a unique selection of (early onset) familial OA cases that resulted in the identification of high impact mutations in COL6A3 likely causal to OA. The mechanism by which such a mutation increases the risk for OA is unclear, partly because there is substantial genetic variation among the population and lifestyle differences that can affect the development of OA. We propose to develop a novel in vitro system for studying the functional effect of identified OA causal variants on the biochemical and mechanical properties of articular cartilage using genome editing of COL6A3 in induced pluripotent stem cells (iPSCs) and cartilage tissue engineering. Type VI collagen plays a critical role in the function of the chondron – the chondrocyte and its surrounding pericellular matrix – which has been shown the regulate the biological and biomechanical environment of chondrocytes in articular cartilage. We will use a combined experimental and theoretical modeling approach to determine how changes in the physicochemical properties of the PCM with COL6A3 mutation influence the mechanical interactions between the chondrocyte and ECM in chondrogenically differentiated iPSCs. We will examine the early signaling events as well as the long-term influence of COL6A3 knockout or mutation on chondrocyte response to loading. Finally, we will examine the effect of the COL6A3 knockout or mutation on the epigenetically controlled changes of the transcriptome of chondrocytes in response to loading. A detailed understanding of these mechanisms will provide critical insight into the development of new pharmacologic, regenerative, or physical therapies for OA.