Fernandes J C, Martel-Pelletier J, Otterness I G, Lopez-Anaya A, Mineau F, Tardif G, Pelletier J P
University of Montreal, Louis-Charles Simard Research Center, Notre-Dame Hospital, Quebec, Canada.
Arthritis Rheum. 1995 Sep;38(9):1290-303. doi: 10.1002/art.1780380918.
To examine the effects of tenidap and diclofenac on osteoarthritic lesions and metalloprotease activity in experimental osteoarthritis (OA).
The anterior cruciate ligament of the right stifle joint of 25 mongrel dogs was sectioned by a stab wound. Seven dogs received no treatment, 6 were treated with oral omeprazole (20 mg/day), another 6 were treated with diclofenac (0.25 mg/kg/twice daily) plus omeprazole (20 mg/day), and 6 received oral tenidap (3 mg/kg/twice daily) plus omeprazole (20 mg/day). The dogs received medication for 8 weeks; all dogs were killed at the end of this period. Eight normal dogs were used as controls. Lesions were evaluated macroscopically for the incidence and size of osteophytes and the area and grade of cartilage erosions on the condyles and plateaus, along with histologic evaluation of the severity of the cartilage lesions and synovial inflammation. Stromelysin and collagenase activities and the collagenase messenger RNA (mRNA) level were measured in cartilage and synovial membrane.
Compared with the untreated or omeprazole-treated OA groups, the dogs treated with tenidap exhibited significant reduction in the incidence (P < or = 0.001) and size (P < or = 0.0001) of osteophytes. Tenidap also significantly decreased the size and grade of cartilage macroscopic lesions, as well as the histologic severity of cartilage lesions on both condyles and plateaus. The histologic severity of synovial inflammatory reaction was also significantly reduced (P < or = 0.003) in the tenidap group. Tenidap markedly decreased stromelysin and collagenase activity in both cartilage (stromelysin P < or = 0.003; collagenase P < or = 0.01) and synovial membrane (stromelysin P < or = 0.003; collagenase P < or = 0.005). Moreover, tenidap also decreased the collagenase mRNA level in cartilage (P < or = 0.005) and synovial membrane (P < or = 0.002). Diclofenac slightly reduced the incidence and size of osteophytes and cartilage lesions, but these changes were not statistically significant. Diclofenac had no effect on the severity of synovial inflammation, metalloprotease activity, or collagenase expression.
This study showed that tenidap had a more potent anti-osteoarthritic effect than diclofenac in this model. The effect of the drug in suppressing metalloprotease synthesis, a process known to play a major role in the pathophysiology of osteoarthritic lesions, may explain its mechanism of action.
研究替硝唑和双氯芬酸对实验性骨关节炎（OA）骨关节炎性病变和金属蛋白酶活性的影响。
25只杂种犬右膝关节前交叉韧带通过刺伤切断。7只犬未接受治疗，6只犬口服奥美拉唑（20mg/天），另外6只犬接受双氯芬酸（0.25mg/kg/每日两次）加奥美拉唑（20mg/天）治疗，6只犬口服替硝唑（3mg/kg/每日两次）加奥美拉唑（20mg/天）。犬接受药物治疗8周；在此期间结束时所有犬均被处死。8只正常犬用作对照。对病变进行宏观评估，观察骨赘的发生率和大小以及髁和平台处软骨侵蚀的面积和分级，同时对软骨病变和滑膜炎症的严重程度进行组织学评估。测量软骨和滑膜中的基质溶解素和胶原酶活性以及胶原酶信使核糖核酸（mRNA）水平。
与未治疗或接受奥美拉唑治疗的OA组相比，接受替硝唑治疗的犬骨赘的发生率（P≤0.001）和大小（P≤0.0001）显著降低。替硝唑还显著降低了软骨宏观病变的大小和分级以及髁和平台处软骨病变的组织学严重程度。替硝唑组滑膜炎症反应的组织学严重程度也显著降低（P≤0.003）。替硝唑显著降低了软骨（基质溶解素P≤0.003；胶原酶P≤0.01）和滑膜（基质溶解素P≤0.003；胶原酶P≤0.005）中的基质溶解素和胶原酶活性。此外，替硝唑还降低了软骨（P≤0.005）和滑膜（P≤0.002）中的胶原酶mRNA水平。双氯芬酸略微降低了骨赘和软骨病变的发生率和大小，但这些变化无统计学意义。双氯芬酸对滑膜炎症的严重程度、金属蛋白酶活性或胶原酶表达无影响。
本研究表明，在该模型中替硝唑比双氯芬酸具有更强的抗骨关节炎作用。该药物在抑制金属蛋白酶合成方面的作用，这一过程在骨关节炎性病变的病理生理学中起主要作用，可能解释了其作用机制。
