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。标志性的症状是关节僵硬和伴有疼痛的肿胀，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，半月板撕裂和骨改造。似乎有一个临床共识，即任何可以预防或逆转软骨损失的治疗方法最有可能为患者提供长期结构和有症状的好处。在寻找OA的中央疾病途径时，异常的软骨细胞肥大已成为一种可能的候选者。在此范式中，OA是由关节软骨细胞的“激活”引起到肥厚和自溶表型的，从而降解了软骨。然而，对正常和OA中基因表达的最新研究强烈支持这样的论点，即软骨破坏是由增强的TGF？1诱导的纤维化基因表达而不是细胞分化为肥大表型的。我们的研究正在解决一个中心问题：TGF？1信号传导一方面导致纤维化的机制是什么机制，另一方面是对软骨修复的修复？软骨侵蚀。生物力学诱导的OA。为了实现这些目标，我们使用的是纤维化和软骨基因的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进行定量软骨深度和表面分析。