Cartilage Degeneration and Repair By ADAMTSs and Hyaluronan Binding Proteins

ADAMTS 和透明质酸结合蛋白的软骨退变和修复

• 批准号: 8457142
• 负责人: ANNA H. PLAAS
• 金额: $ 32.7万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8457142
• 关键词: ADAMTS; Ablation; Address; Aging; Arthritis; BMP7 gene; CD44 Antigens; Cartilage; Cartilage injury; Cell Differentiation process; Cells; Chondrocytes; Chondrogenesis; Cleaved cell; Clinical; Complement; Complex; Consensus; Degenerative polyarthritis; Development; Disease Pathway; Effectiveness; Endocytosis; Event; Fibroblasts; Fibrosis; Focal Adhesions; Gene Expression; Genes; Heredity; Human; Hyaluronan; Hypertrophy; Injectable; Joints; Knee; Knockout Mice; Laser Microscopy; MAP3K1 gene; MAPK8 gene; Mediating; Mediator of activation protein; Mesenchymal; Mesenchymal Stem Cells; Microscopy; Modeling; Mus; Myofibroblast; Normal Cell; Obesity; PTK2 gene; Pain; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Phosphorylation; Photons; Quality of life; Research; Risk Factors; Role; Route; Signal Transduction; Small Interfering RNA; Structure; Surface; Swelling; Symptoms; TGF-beta type I receptor; Tissues; aggrecan; cartilage cell; cartilage repair; cell associated matrix; cell type; cellular targeting; effective therapy; improved; in vivo; inhibitor/antagonist; joint injury; joint stiffness; knockout gene; prevent; progenitor; receptor; repaired; response; uptake

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.

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，并伴有进行性组织变化，包括软骨侵蚀、滑膜纤维化、半月板撕裂和骨重塑。临床似乎达成共识，任何可以预防或逆转软骨损失的治疗最有可能为患者提供长期的结构和症状益处。在寻找 OA 的主要疾病途径时，异常软骨细胞肥大已成为一种可能的候选途径。在这个范例中，OA是由于关节软骨细胞“激活”肥大和自溶表型而导致软骨降解的结果。然而，最近对正常和 OA 软骨中基因表达的多项研究强烈支持这样的论点，即软骨破坏是由于 TGFβ1 诱导的促纤维化基因表达增强而不是细胞分化为肥大表型所致。我们的研究正在解决这个核心问题：TGF?1 信号传导一方面导致纤维化，另一方面导致软骨修复的机制是什么？”如果详细了解这一机制，它似乎为干预 OA 的发生和进展提供了独特的治疗机会。我们最近对小鼠 OA 模型的研究表明，ADAMTS5 的基因敲除可以非常有效地预防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，它裂解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 生物力学诱发的 OA。我们还在比较目前临床使用的关节内注射剂（BMP7 和 HA）在小鼠 OA 模型中阻止纤维化和增强软骨形成的能力。为了实现这些目标，我们使用纤维形成和软骨形成基因的 QPCR、基因表达的 siRNA 沉默、细胞的共聚焦和 2 光子显微镜以及 ?CT 定量软骨深度和表面分析。