Boileau Christelle, Martel-Pelletier Johanne, Fahmi Hassan, Mineau François, Boily Martin, Pelletier Jean-Pierre
University of Montreal Hospital Centre, Notre-Dame Hospital, Montreal, Quebec, Canada.
Arthritis Rheum. 2007 Jul;56(7):2288-98. doi: 10.1002/art.22726.
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.
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.
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.
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.
新出现的证据表明，过氧化物酶体增殖物激活受体γ（PPARγ）可能对骨关节炎（OA）具有保护作用。本研究的目的是评估PPARγ激动剂吡格列酮在犬OA模型中对病变发展的体内作用，并探讨吡格列酮对OA病理生理变化中主要信号传导和代谢途径的影响。
通过切断前交叉韧带手术诱导犬发生OA。然后将犬随机分为3个治疗组，分别口服给予安慰剂、15mg/天吡格列酮或30mg/天吡格列酮，持续8周。治疗后，对软骨损伤的严重程度进行评分。对软骨标本进行组织学和免疫组织化学评估；使用特异性抗体研究基质金属蛋白酶1（MMP-1）、含血小板解聚蛋白样金属蛋白酶5（ADAMTS-5）和诱导型一氧化氮合酶（iNOS）的水平，以及磷酸化的丝裂原活化蛋白激酶ERK-1/2、p38、JNK和核因子κB p65。
吡格列酮以剂量依赖性方式减少软骨损伤的发展，最高剂量产生统计学上的显著变化（P<0.05）。损伤的减少与较低的软骨组织学评分相关。此外，吡格列酮显著降低了OA关键介质MMP-1、ADAMTS-5和iNOS的合成，同时抑制了丝裂原活化蛋白激酶ERK-1/2、p38和核因子κB的信号通路激活。
这些结果表明吡格列酮在体内减少软骨损伤方面具有疗效。这些结果还为OA的治疗干预提供了新的有趣见解，即PPARγ激活可抑制炎症的主要信号通路，并减少负责关节软骨降解的软骨分解因子的合成。
