INSERM UMR-S 957, 1 rue Gaston Veil, 44035, Nantes Cedex 1, France.
Arthritis Res Ther. 2009;11(6):R185. doi: 10.1186/ar2877. Epub 2009 Dec 10.
Osteoclasts play a key role in the pathogenesis of bone erosion and systemic bone mass loss during rheumatoid arthritis (RA). In this study, we aimed to determine the effect of methotrexate (MTX) and zoledronic acid (ZA), used alone or in combination, on osteoclast-mediated bone erosions and systemic bone mass loss in a rat model of collagen induced arthritis (CIA). We hypothesized that MTX and ZA could have an additive effect to prevent both bone erosion and systemic bone loss.
Arthritis was induced in 64 female Sprague-Dawley rats. After the clinical onset of CIA, rats were assigned to treatment with MTX (1 mg/kg/week), ZA (100 microg/kg twice weekly), both treatments at the same regimens, or vehicle. Arthritis score and paw thickness were recorded twice weekly. The rats were sacrificed on D28 and hind paws were removed for radiographic, histological and immunohistochemical analysis. The effects of treatments on osteoclastogenesis were determined by Tartrate resistant acid phosphatase (TRAP) staining. Micro-CT of the tibia was carried out for histomorphometric analysis. Bone mass density was evaluated by densitometry.
MTX significantly decreased the severity of CIA, whereas ZA slightly exacerbated it. When these two drugs were used in combination, MTX prevented the pro-inflammatory effect of ZA. The combination of ZA with MTX was more effective than MTX alone for reducing structural joint damage with a dramatic decrease of osteoclasts' number in the eroded joints. However, MTX alone also significantly reduced the number of osteoclasts and the number of CD68+ mononuclear cells. ZA alone, or ZA with MTX, significantly increased the systemic bone mass density measured by densitometry and bone volume on histomorphometric analysis.
A combination of MTX and ZA prevented both bone erosion and systemic bone loss in a rat model of arthritis. Both treatments independently decreased the number of osteoclasts in the eroded joint. However, while MTX probably acts mainly through a decrease of inflammation, ZA has a direct effect on osteoclasts, allowing a dramatic down-regulation of these cells in inflamed joints. These two different mechanisms of action provide support for the use of a combination of these two drugs to improve the prevention of structural joint damage in RA.
破骨细胞在类风湿关节炎（RA）的骨侵蚀和全身骨量丢失的发病机制中起关键作用。在这项研究中，我们旨在确定甲氨蝶呤（MTX）和唑来膦酸（ZA）单独或联合使用对胶原诱导性关节炎（CIA）大鼠模型中破骨细胞介导的骨侵蚀和全身骨量丢失的影响。我们假设 MTX 和 ZA 可以具有预防骨侵蚀和全身骨质流失的附加作用。
在 64 只雌性 Sprague-Dawley 大鼠中诱导关节炎。在 CIA 临床发作后，将大鼠分配接受 MTX（1mg/kg/周）、ZA（100μg/kg 每周两次）、相同方案的两种治疗或载体治疗。每周两次记录关节炎评分和爪厚度。在 D28 处死大鼠，切除后爪进行放射照相、组织学和免疫组织化学分析。通过抗酒石酸酸性磷酸酶（TRAP）染色确定治疗对破骨细胞生成的影响。对胫骨进行微 CT 以进行组织形态计量学分析。通过密度测定法评估骨量密度。
MTX 显著降低 CIA 的严重程度，而 ZA 则略有加重。当将这两种药物联合使用时，MTX 可预防 ZA 的促炎作用。与 MTX 单独使用相比，ZA 与 MTX 的联合使用在降低结构性关节损伤方面更有效，并且在侵蚀关节中破骨细胞的数量明显减少。然而，MTX 单独使用也显著降低了破骨细胞的数量和 CD68+单核细胞的数量。ZA 单独使用或与 MTX 联合使用均显著增加了通过密度测定法测量的全身骨量密度和组织形态计量学分析中的骨体积。
MTX 和 ZA 的联合治疗可预防关节炎大鼠模型中的骨侵蚀和全身骨丢失。两种治疗均独立地降低了侵蚀关节中破骨细胞的数量。然而，虽然 MTX 可能主要通过降低炎症起作用，但 ZA 对破骨细胞具有直接作用，从而使这些细胞在发炎关节中急剧下调。这两种不同的作用机制为联合使用这两种药物以改善 RA 中结构关节损伤的预防提供了支持。
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