Pioglitazone, a peroxisome proliferator-activated receptor gamma agonist, reduces the progression of experimental osteoarthritis in guinea pigs.
OBJECTIVE
To evaluate the in vivo therapeutic effect of pioglitazone, a peroxisome proliferator-activated receptor gamma (PPARgamma) 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-1beta (IL-1beta) 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-1beta 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-1beta 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-1beta in OA cartilage.


CONCLUSIONS
This is the first in vivo study demonstrating that a PPARgamma agonist, pioglitazone, could reduce the severity of experimental OA. This effect was associated with a reduction in the levels of MMP-13 and IL-1beta, which are known to play an important role in the pathophysiology of OA lesions.
Kobayashi
Tetsuya
T
Takeda Pharmaceutical Co. Ltd., Osaka, Japan.
Notoya
Kohei
K
Naito
Takako
T
Unno
Satoko
S
Nakamura
Akihiro
A
Martel-Pelletier
Johanne
J
Pelletier
Jean-Pierre
JP
D000284:Administration, Oral; D000818:Animals; D002358:Cartilage, Articular / Q000378:metabolism / Q000473:pathology; D017364:Collagenases / Q000096:biosynthesis; D004195:Disease Models, Animal; D018450:Disease Progression; D006168:Guinea Pigs; D007150:Immunohistochemistry; D007375:Interleukin-1 / Q000096:biosynthesis; D008297:Male; D053509:Matrix Metalloproteinase 13; D010003:Osteoarthritis / Q000503:physiopathology*; D047495:PPAR gamma / Q000819:agonists*; D000077205:Pioglitazone; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use
D007375:Interleukin-1; D047495:PPAR gamma; D045162:Thiazolidinediones; D017364:Collagenases; D053509:Matrix Metalloproteinase 13; D000077205:Pioglitazone