Adult Cartilage-Specific Peroxisonrie Proliferator-Activated Receptor Gamma Knockout Mice Exhibit the Spontaneous Osteoarthritis Phenotype

Osteoarthritis (OA) is an age-related progressive degenerative joint disease. Peroxisome pro-Liferator-activated receptor gamma (PPAR gamma), a transcription factor, is suggested as an attractive therapeutic target to counteract degradative mechanisms associated with OA. Studies suggest that activation of PPAR gamma by its agonists can reduce the synthesis of OA catabolic and inflammatory factors and the development of cartilage Lesions in OA animal models. Because these agonists impart several PPAR gamma-independent effects, the specific in vivo function of PPAR gamma in cartilage homeostasis and OA remains largely unknown. Herein, we describe the in vivo role of PPAR gamma in OA using cartilage-specific PPAR gamma knockout (KO) mice generated using the Cre-Lox system. Adult PPAR gamma KO mice exhibited a spontaneous OA phenotype associated with enhanced cartilage degradation, hypocellularity, synovial and cartilage fibrosis, synovial inflammation, mononuclear cell influx in the synovium, and increased expression of catabolic factors, including matrix metalloproteinase-13, accompanied by an increase in staining for matrix metalloproteinase-generated aggrecan and type II collagen neoepitopes (VDIPEN and C1-2C). We demonstrate that PPAR gamma-deficient articular cartilage exhibits elevated expression of the additional catabolic factors hypoxia-inducible factor-2 alpha, syndecan-4, and a disintegrin and metalloproteinase with thrombospondin motifs 5 and of the inflammatory factors cyclooxygenase-2 and inducible nitric oxide synthase. In conclusion, PPAR gamma is a critical regulator of cartilage health, the lack of which Leads to an accelerated spontaneous OA phenotype.