Mechanism of bone and joint destruction in rheumatoid arthritis. Effect of mechanical stress on synovial cells.

滑膜组织被认为是类风湿关节炎(RA)的主要炎症部位。滑膜组织存在于关节囊内，随着关节的运动，滑膜组织扩张或松弛。这表明滑膜组织暴露在机械应力下，然而，机械应力对滑膜组织的影响还不是很清楚。我们使用Flexercell系统对滑膜细胞施加膨胀应力。类风湿滑膜细胞种植在I型胶原涂层的软底支架上，随着机械应力的变化，滑膜细胞的形状发生了变化。机械应激诱导细胞内信号转导，涉及小GTP蛋白、Rho、Rac、Ras通路。氨基双膦酸盐，阿伦磷酸，抑制小GTP蛋白的前烯基化，延缓RA患者骨侵蚀的进展。服用阿仑磷酸钠的类风湿关节炎患者对髋关节和膝关节的骨质和关节破坏的易感性较低。探讨机械应力方向与边缘侵蚀形成部位的关系。食指尺侧和食指桡侧可能形成较多的侵蚀。食指尺侧和食指放射侧被认为更容易受到扩张性应力的影响。肌腱周围的滑膜组织衬里对扩张性机械应力也很敏感。培养的滑膜细胞分化为破骨细胞样细胞，在牙本质片上形成吸收陷窝。来自腱鞘的滑膜细胞表达MMP1、2、3、13和TIMP1、2，并表达肿瘤坏死因子α、白介素1β、白介素6和RANKL。提示机械应激刺激滑膜细胞表达促炎细胞因子、RANKL和MMPs，从而不仅加重滑膜炎症，而且加重关节破坏。

Synovial tissue is believe to be a main site of inflammation in rheumatoid arthritis (RA). Synovial tissue exists to line joint capsule, so the tissue is expand or relaxed in accordance with joint motion. That suggests synovial tissue is exposed to mechanical stress, however, the effect of mechanical stress on synovial tissue is not well understood. We used Flexercell system to apply expansile stress on synovial cells. Rheumatoid synovial cells seeded on type I collagen-coated flexible-bottomed well changed the shape in response to the mechanical stress. Mechanical stress induces intracellular signaling which involves small GTP protein, Rho, Rac, Ras pathway. Aminobisphosphonate, alendronate, inhibits prenylation of the small GTP protein, retards progression of bone erosion in RA patients. The RA patients who intake alendronate are tend to less susceptible to bone and joint destruction in hip and knee joints. To examine the relationship between the direction of mechanical stress and site of marginal erosion formation. More erosion is likely to be formed in ulnar side of first finger and radial side of second finger. Ulnar side of first finger and radial side of second finger are thought to be more susceptible to expansile stress. Synovial tissue lining around tendon is also susceptible to expansile mechanical stress. Cultured synovial cells differentiated to osteoclast-like cells, which formed resorption pits on dentine slice. Synovial cells derived from tendon sheath expressed MMP-1,2,3,13 and TIMP-1,2. Moreover, the cells also expressed TNF-α, IL-1β, IL-6 and RANKL. It is suggested that mechanical stress stimulates synovial cells to express pro-inflammatory cytokine and RANKL, as well as MMPs, thereby enhancing not only synovial inflammation, but joint destruction.