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.
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.
