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Objective. Emerging evidence indicates that peroxisome proliferator-activated receptor ␥ (PPAR␥) may have protective effects in osteoarthritis (OA). The aim of this study was to evaluate the in vivo effect of a PPAR␥ agonist, pioglitazone, on the development of lesions in a canine model of OA, and to explore the influence of pioglitazone on the major signaling and metabolic pathways involved in OA pathophysiologic changes.Methods. OA was surgically induced in dogs by sectioning of the anterior cruciate ligament. The dogs were then randomly divided into 3 treatment groups in which they were administered either placebo, 15 mg/day pioglitazone, or 30 mg/day pioglitazone orally for 8 weeks. Following treatment, the severity of cartilage lesions was scored. Cartilage specimens were processed for histologic and immunohistochemical evaluations; specific antibodies were used to study the levels of matrix metalloproteinase 1 (MMP-1), ADAMTS-5, and inducible nitric oxide synthase (iNOS), as well as phosphorylated MAPKs ERK-1/2, p38, JNK, and NF-B p65.Results. Pioglitazone reduced the development of cartilage lesions in a dose-dependent manner, with the highest dosage producing a statistically significant change (P < 0.05). This decrease in lesions correlated with lower cartilage histologic scores. In addition, pioglitazone significantly reduced the synthesis of the key OA mediators MMP-1, ADAMTS-5, and iNOS and, at the same time, inhibited the activation of the signaling pathways for MAPKs ERK-1/2, p38, and NF-B.Conclusion. These results indicate the efficacy of pioglitazone in reducing cartilage lesions in vivo. The results also provide new and interesting insights into a therapeutic intervention for OA in which PPAR␥ activation can inhibit major signaling pathways of inflammation and reduce the synthesis of cartilage catabolic factors responsible for articular cartilage degradation.Osteoarthritis (OA), one of the most common arthritic conditions, is primarily related to the progressive erosion of articular cartilage associated with synovial inflammation. The changes in cartilage are linked to a combination of mechanical and biochemical factors (1). The subchondral bone remodeling that takes place during the evolution of OA is believed to be an important factor in cartilage degradation (2-4). Its contribution seems to be associated with both the abnormal biophysical properties of the tissue and the excess synthesis of many catabolic factors, including growth hormones and cytokines, that can modulate the metabolism of OA cartilage (5-8).

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