Cartilage Degeneration and Repair By ADAMTSs and Hyaluronan Binding Proteins

描述（由申请人提供）：骨关节炎（OA）的危险因素包括关节损伤、肥胖、衰老和遗传。标志性症状是关节僵硬和肿胀并伴有疼痛，并伴有进行性组织改变，包括软骨侵蚀、滑膜纤维化、半月板撕裂和骨重塑。临床似乎一致认为，任何能够预防或逆转软骨丢失的治疗都最有可能为患者提供长期的结构和症状益处。在寻找骨性关节炎的中心疾病途径时，异常软骨细胞肥大已成为一个可能的候选者。在这种情况下，骨性关节炎是由关节软骨细胞的“活化”导致软骨的肥厚和自溶表型。然而，最近对正常软骨和OA软骨中基因表达的多项研究强烈支持软骨破坏是由TGF？1诱导的纤维化基因表达，而不是从细胞分化到肥厚表型。我们的研究正在解决一个核心问题：TGF的机制是什么？1号信号一方面导致纤维化，另一方面导致软骨修复？”如果详细了解这一机制，似乎将为OA的发生和发展提供独特的干预治疗机会。我们最近对小鼠OA模型的研究表明，敲除ADAMTS5基因可以非常有效地防止关节周围组织纤维化和软骨侵蚀。ADAMTS5的致病作用似乎主要是由于其在间充质软骨祖细胞周围的活性，在那里它分裂聚集蛋白并促进它们分化成肌成纤维细胞而不是软骨细胞。为了研究这一途径，我们使用条件消融ADAMTS5，特别是间充质祖细胞，以确定该方法是否能保护小鼠免受生物力学诱导的OA。我们还比较了目前在临床使用的关节内注射剂（BMP7和HA）在小鼠OA模型中阻断纤维化和促进软骨形成的能力。为了实现这些目标，我们使用了纤维性和软骨性基因的QPCR，基因表达的siRNA沉默，细胞的共聚焦和双光子显微镜和？CT定量软骨深度和表面分析。

DESCRIPTION (provided by applicant): Risk factors for osteoarthritis (OA) include joint injury, obesity, aging and heredity. Hallmark symptoms are joint stiffness and swelling with associated pain, and these are accompanied by progressive tissue changes which include cartilage erosion, synovial fibrosis, meniscal tears and bony remodeling. There appears to be a clinical consensus that any treatment which can prevent or reverse cartilage loss is most likely to provide long-term structural and symptomatic benefit for the patient. In the search for a central disease pathway for OA, abnormal chondrocyte hypertrophy has emerged as one possible candidate. In this paradigm, OA results from an "activation" of articular chondrocytes to the hypertrophic and autolytic phenotype which degrades the cartilage. However, multiple recent studies of gene expression in normal and OA cartilages strongly support the contention that the cartilage destruction results from an enhanced TGF?1-induced profibrotic gene expression rather than from differentiation of cells to a hypertrophic phenotype. Our research is addressing the central question: What is the mechanism by which TGF?1 signaling leads to fibrosis on the one hand and cartilage repair on the other?" If this mechanism was understood in detail, it would seem to offer a unique opportunity to intervene therapeutically in OA initiation and progression. Our recent studies with murine OA models, have illustrated that gene knockout of ADAMTS5 very effectively prevents fibrosis of periarticular joint tissues and cartilage erosion. The pathogenic role of ADAMTS5 appears to be primarily due to its activity around mesenchymal chondroprogenitors, where it cleaves aggrecan and promotes their differentiation to myofibroblasts rather than chondrocytes. To investigate this pathway we are using conditional ablation of ADAMTS5, specifically in mesenchymal progenitor cells, to determine if this approach will protect mice from biomechanically-induced OA. We are also comparing the capacity of intra-articular injectables (BMP7 and HA), which are currently in clinical use, to block fibrosis and enhance chondrogenesis in murine OA models. To achieve these objectives we are using QPCR of fibrogenic and chondrogenic genes, siRNA silencing of gene expression, confocal and 2-photon microscopy of cells and ?CT for quantitative cartilage depth and surface analysis.