Pelletier Jean-Pierre, Fernandes Julio C, Brunet Julie, Moldovan Florina, Schrier Denis, Flory Craig, Martel-Pelletier Johanne
Hôpital Notre-Dame, Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada.
Arthritis Rheum. 2003 Jun;48(6):1582-93. doi: 10.1002/art.11014.
OBJECTIVE: The primary aim of this study was to investigate, using an experimental rabbit model of osteoarthritis (OA), the effect of a selective mitogen-activated protein kinase kinase 1/2 (MEK-1/2) inhibitor, PD 198306, on the development of structural changes. Additional aims were to assess the effects of the inhibitor on levels of phosphorylated extracellular signal-regulated kinase 1/2 (phospho-ERK-1/2) and matrix metalloproteinase 1 (MMP-1; collagenase 1) in OA chondrocytes. METHODS: After surgical sectioning of the anterior cruciate ligament of the right knee joint, rabbits with OA were separated into 3 experimental groups: oral treatment with placebo or with PD 198306 at a therapeutic concentration of 10 mg/kg/day or 30 mg/kg/day. Each treatment started immediately after surgery. The animals were killed 8 weeks after surgery. Macroscopic and histologic studies were performed on the cartilage and synovial membrane. The levels of phospho-ERK-1/2 and MMP-1 in OA cartilage chondrocytes were evaluated by immunohistochemistry. Normal, untreated rabbits were used as controls. RESULTS: OA rabbits treated with the highest dosage of MEK-1/2 inhibitor showed decreases in the surface area (size) of cartilage macroscopic lesions (P < 0.002) and in osteophyte width on the lateral condyles (P = 0.05). Histologically, the severity of synovial inflammation (villous hyperplasia) was also reduced (P < 0.02). In cartilage from placebo-treated OA rabbits, a significantly higher percentage of chondrocytes in the superficial layer stained positive for phospho-ERK-1/2 and MMP-1 compared with normal controls. Rabbits treated with the highest dosage of PD 198306 demonstrated a significant and dose-dependent reduction in the level of phospho-ERK-1/2 and a lower level of MMP-1. CONCLUSION: This study demonstrates that, in vivo, PD 198306, a selective inhibitor of MEK-1/2, can partially decrease the development of some of the structural changes in experimental OA. This effect was associated with a reduction in the level of phospho-ERK-1/2 in OA chondrocytes, which probably explains the action of the drug.
目的：本研究的主要目的是利用骨关节炎（OA）实验兔模型，研究选择性丝裂原活化蛋白激酶激酶1/2（MEK - 1/2）抑制剂PD 198306对结构变化发展的影响。其他目的是评估该抑制剂对OA软骨细胞中磷酸化细胞外信号调节激酶1/2（磷酸化ERK - 1/2）和基质金属蛋白酶1（MMP - 1；胶原酶1）水平的影响。 方法：在对右膝关节前交叉韧带进行手术切断后，将患OA的兔子分为3个实验组：口服安慰剂或口服治疗浓度为10 mg/kg/天或30 mg/kg/天的PD 198306。每种治疗在手术后立即开始。动物在手术后8周处死。对软骨和滑膜进行宏观和组织学研究。通过免疫组织化学评估OA软骨细胞中磷酸化ERK - 1/2和MMP - 1的水平。正常、未治疗的兔子用作对照。 结果：用最高剂量MEK - 1/2抑制剂治疗的OA兔子，软骨宏观病变的表面积（大小）减小（P < 0.002），外侧髁骨赘宽度减小（P = 0.05）。组织学上，滑膜炎症（绒毛增生）的严重程度也降低（P < 0.02）。与正常对照相比，安慰剂治疗的OA兔子软骨中，表层软骨细胞中磷酸化ERK - 1/2和MMP - 1染色阳性的百分比显著更高。用最高剂量PD 198306治疗的兔子，磷酸化ERK - 1/2水平显著且呈剂量依赖性降低，MMP - 1水平较低。 结论：本研究表明，在体内，MEK - 1/2的选择性抑制剂PD 198306可部分减少实验性OA中某些结构变化的发展。这种作用与OA软骨细胞中磷酸化ERK - 1/2水平的降低有关，这可能解释了该药物的作用机制。
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