Pioglitazone, a peroxisome proliferator–activated receptor γ agonist, reduces the progression of experimental osteoarthritis in guinea pigs

Abstract

Objective. To evaluate the in vivo therapeutic effect of pioglitazone, a peroxisome proliferatoractivated receptor ␥ (PPAR␥) agonist, on the development of lesions in a guinea pig model of osteoarthritis (OA), and to determine the influence of pioglitazone on the synthesis of matrix metalloproteinase 13 (MMP-13) and interleukin-1␤ (IL-1␤) in articular cartilage.Methods. The OA model was created by partial medial meniscectomy of the right knee joint. The guinea pigs were divided into 4 treatment groups: unoperated animals that received no treatment (normal), operated animals (OA guinea pigs) that received placebo, OA guinea pigs that received oral pioglitazone at 2 mg/kg/ day, and OA guinea pigs that received oral pioglitazone at 20 mg/kg/day. The animals began receiving medication 1 day after surgery and were killed 4 weeks later. Macroscopic and histologic analyses were performed on the cartilage. The levels of MMP-13 and IL-1␤ in OA cartilage chondrocytes were evaluated by immunohistochemistry.Results. OA guinea pigs treated with the highest dosages of pioglitazone showed a significant decrease, compared with the OA placebo group, in the surface area (size) and grade (depth) of cartilage macroscopic lesions on the tibial plateaus. The histologic severity of cartilage lesions was also reduced. A significantly higher percentage of chondrocytes in the middle and deep layers stained positive for MMP-13 and IL-1␤ in cartilage from placebo-treated OA guinea pigs compared with normal controls. Guinea pigs treated with the highest dosage of pioglitazone demonstrated a significant reduction in the levels of both MMP-13 and IL-1␤ in OA cartilage.Conclusion. This is the first in vivo study demonstrating that a PPAR␥ agonist, pioglitazone, could reduce the severity of experimental OA. This effect was associated with a reduction in the levels of MMP-13 and IL-1␤, which are known to play an important role in the pathophysiology of OA lesions.Osteoarthritis (OA) is a degenerative disease and the major cause of disability in humans. Aging, mechanical stress and traumatic injury, genetic susceptibility, and metabolic predispositions are considered risk factors for this disease. An important feature of OA is the degradation of articular cartilage, composed of abundant extracellular matrix rich in sulfated proteoglycan and type II collagen. This process is likely related to the excess synthesis and release of several catabolic factors such as proinflammatory cytokines, matrix metalloproteinases (MMPs), and nitric oxide (NO) in the tissue (1).OA is characterized by a shift of the balance between production of cartilage matrix and proteolytic degradation toward increased proteolysis. The most influential causative proteases in OA are MMPs, a family of zinc-containing, calcium-dependent proteases. An MMP that is of particular interest in the degradation of cartilage in pathologic conditions is MMP-13 (collagenase 3). MMP-13 has been found to be elevated in both rheumatoid arthritis (RA) and OA joint tissues and, more particularly, ...

The 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

“…This effect was mainly related to a reduction in the severity of structural changes and loss of matrix aggrecans, as shown by the protective effect of the drug on the loss of Safranin O staining. These findings are again consistent with those by Kobayashi et al (19) in the guinea pig model, and suggest that pioglitazone treatment has significant positive effects on major OA cartilage catabolic processes.…”

“…In the present study, pioglitazone was found to preferentially reduce the development of cartilage lesions on the femoral condyles. These findings are very much in accordance with those previously reported in a study in which pioglitazone was used as treatment in a guinea pig model of medial meniscectomy-induced OA (19). In the latter model, the protective effects of the drug were noted on the medial tibial plateaus, which is to be expected, since the lesions are preferentially distributed at that anatomic site in the guinea pig model.…”

“…The inhibition of MMP-1 production was found to be associated with a reduction in activator protein 1 (AP-1) binding activity (16). In vivo, in the guinea pig OA model, treatment with pioglitazone was found to reduce the levels of IL-1␤ and MMP-13 in cartilage chondrocytes (19).…”

“…This action of the PPAR␥ agonists is mediated through the inhibition of a number of signaling pathways, including the NF-B and MAPK pathways (17,18). A recent study has provided preliminary evidence that pioglitazone, a PPAR␥ agonist, can reduce the progression of experimental OA in a guinea pig model of meniscectomyinduced arthritis (19).…”

Prevalence of the Pro12Ala missense mutation in the PPARG2 gene in Kuwaiti patients with primary knee osteoarthritis

“…There is also some evidence to suggest that PPARG2 activation may be chondroprotective by negatively regulating the expression of matrix metalloproteinase-1 and matrix metalloproteinase-13 and by preventing proteoglycan degradation 4589. It has also been shown that treatment with a PPARG2 activator, pioglitazone, shows beneficial effects in an experimental model of OA 10. Therefore, it has been postulated that PPARG2 could be a candidate gene for susceptibility to OA.…”