Cartilage Degeneration and Repair By ADAMTSs and Hyaluronan Binding Proteins

描述（由申请人提供）：骨关节炎（OA）的风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，伴有疼痛，这些症状伴随着进行性组织变化，包括软骨侵蚀、滑膜纤维化、关节撕裂和骨重塑。似乎有一个临床共识，任何治疗，可以防止或逆转软骨损失是最有可能提供长期的结构和症状的好处，为病人。在寻找OA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。在这种模式中，OA是由关节软骨细胞“活化”为肥大和自溶表型导致的，其降解软骨。然而，多个最近的研究，在正常和OA软骨的基因表达强烈支持的论点，软骨破坏的结果，从增强TGF？1-诱导促纤维化基因表达，而不是从细胞分化为肥大表型。我们的研究正在解决一个中心问题：TGF的机制是什么？1信号一方面导致纤维化，另一方面导致软骨修复？“如果详细了解这种机制，它似乎提供了一个独特的机会来治疗OA的开始和进展。我们最近对小鼠OA模型的研究表明，ADAMTS5基因敲除非常有效地防止了关节周围关节组织的纤维化和软骨侵蚀。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，在那里它切割聚集蛋白聚糖并促进其分化为肌成纤维细胞而不是软骨细胞。为了研究这一途径，我们正在使用ADAMTS5的条件性消融，特别是在间充质祖细胞中，以确定这种方法是否会保护小鼠免受生物力学诱导的OA。我们还比较了目前临床使用的关节内注射剂（BMP 7和HA）在小鼠OA模型中阻断纤维化和增强软骨形成的能力。为了实现这些目标，我们正在使用QPCR的纤维化和软骨形成基因，siRNA沉默的基因表达，共聚焦和双光子显微镜的细胞和？CT用于定量软骨深度和表面分析。 公共卫生相关性：预防人类骨关节炎中软骨损伤的药物的开发是一个未满足的需求。这些药物应该降低疼痛水平，显着改善生活质量。我们的研究解决了组织表面的软骨细胞为什么以及如何从软骨保护性转变为软骨破坏性的根本问题。这个问题的答案应该最终提供有效治疗所需的细胞“目标”。

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. PUBLIC HEALTH RELEVANCE: The development of agents which prevent cartilage damage in human osteoarthritis is an unmet need. Such medications should lower pain levels and markedly improve quality of life. Our research addresses the fundamental question of why and how cartilage cells at the surface of the tissue switch from being cartilage protective to cartilage destructive. The answer to this question should finally provide the cellular "target" needed for effective treatment.