Open AccessThe peroxisome proliferator–activated receptor γ agonist pioglitazone reduces the development of cartilage lesions in an experimental dog model of osteoarthritis: In vivo protective effects mediated through the inhibition of key signaling and catabolic pathways
Author(s) -
Boileau Christelle,
MartelPelletier Johanne,
Fahmi Hassan,
Mineau François,
Boily Martin,
Pelletier JeanPierre
Publication year - 2007
Publication title -
arthritis & rheumatism
Language(s) - English
Resource type - Journals
eISSN - 1529-0131
pISSN - 0004-3591
DOI - 10.1002/art.22726
Subject(s) - pioglitazone , in vivo , osteoarthritis , agonist , cartilage , endocrinology , medicine , peroxisome proliferator activated receptor , receptor , nitric oxide synthase , pharmacology , nitric oxide , pathology , biology , anatomy , type 2 diabetes , diabetes mellitus , alternative medicine , microbiology and biotechnology
Objective Emerging evidence indicates that peroxisome proliferator–activated receptor γ (PPARγ) may have protective effects in osteoarthritis (OA). The aim of this study was to evaluate the in vivo effect of a PPARγ 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‐κB 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‐κB. 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 PPARγ activation can inhibit major signaling pathways of inflammation and reduce the synthesis of cartilage catabolic factors responsible for articular cartilage degradation.