The peroxisome proliferator-activated receptor gamma 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

Arthritis Rheum. 2007 Jul;56(7):2288-98. doi: 10.1002/art.22726.


Objective: Emerging evidence indicates that peroxisome proliferator-activated receptor gamma (PPARgamma) may have protective effects in osteoarthritis (OA). The aim of this study was to evaluate the in vivo effect of a PPARgamma 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-kappaB 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-kappaB.

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 PPARgamma activation can inhibit major signaling pathways of inflammation and reduce the synthesis of cartilage catabolic factors responsible for articular cartilage degradation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cartilage / drug effects
  • Cartilage / pathology*
  • Disease Models, Animal
  • Dogs
  • Femur
  • Hypoglycemic Agents / therapeutic use
  • Osteoarthritis / drug therapy
  • Osteoarthritis / pathology*
  • PPAR gamma / agonists*
  • Pioglitazone
  • Thiazolidinediones / therapeutic use*
  • Tibia


  • Hypoglycemic Agents
  • PPAR gamma
  • Thiazolidinediones
  • Pioglitazone