1,25(OH)2D3对类风湿关节炎成纤维滑膜细胞IL-22介导的RANKL表达及破骨细胞形成影响的可能机制研究

Rheumatoid arthritis (RA) is a chronic in?ammatory disease that causes erosive arthritis and joint destruction, which can lead to severe disability and increased mortality. The causes of the inappropriate immune activation are not known; however, it is clear that several risk factors play a role. Interleukin-22 (IL-22), as a key inflammatory cytokine, can directly induce RANKL expression through JAK-2/STAT-3 and p38 MAPK/NF-κB RANKL pathway. Therefore IL-22-initiated JAK-2/STAT-3 and p38 MAPK/NF-κB RANKL pathway play a critical role for joint destruction in RA and maybe a good target for therapeutic intervention. There is increasing support for the idea that impaired vitamin D homeostasis contributes to RA processes. 1,25-dihydroxyvitamin D3(1,25(OH)2D3) can modulate immune responses by inhibiting growth and differentiation of dendritic cells and T cells. It remains unknown whether 1,25(OH)2D3 can also directly modulate osteoclast-like cell formation via receptor activator of nuclear factor kappa B ligand (RANKL) expressions in rheumatoid arthritis fibroblast-like synoviocytes(FLS). We observed that patients with RA have decreased levels of 1,25(OH)2D3 and that the levels were lowest in those with increased disease activity score in 28 joints (DAS28), clinical disease activity index (CDAI), C-reactive protein (CRP), swelling joint counts (SJC) and tender joint counts (TJC) suggesting that the possible immunoregulatory role of Vit D in RA. 1,25(OH)2D3 can decrease the level of serum IL-22 and suppress RANKL expression in a dose-dependent manner, ultimately retard the progression of joint damage. To address this possibility, we examined the effects of 1,25(OH)2D3 on FLS responses. We observed 1,25(OH)2D3 can obviously induce apoptosis of memory T cell. But it is indefinite whether the therapeutic of 1,25(OH)2D3 suppress RANKL expression of RA synovial cells. Which component of trans-signaling pathway is a key site of its effect? This study will give the answer.

类风湿关节炎（RA）是一种以残毁性关节炎为主要特征的自身免疫病，破骨细胞活化在RA关节破坏中起主要作用，而滑膜细胞RANKL分泌增加是破骨细胞分化的必要条件。IL-22通过诱导JAK-2/STAT-3 和p38 MAPK/NF-κB信号转导通路的活化促进了RANKL的大量表达。近年研究显示1,25(OH)2D3在调节机体免疫功能方面发挥着重要作用。我们的前期研究发现1,25(OH)2D3参与了RA的免疫反应并与关节炎症有关。同时，1,25(OH)2D3可降低RA患者血清IL-22的水平，并呈剂量依赖性的抑制RANKL表达，从而延缓骨破坏。 本研究以RA患者成纤维滑膜细胞为研究对象， 探讨1,25(OH)2D3是否可以通过阻断上述信号转导途径抑制RA患者滑膜细胞RANKL 的表达，影响破骨细胞的形成，实现对RA患者的骨保护效应，为临床使用1,25(OH)2D3提供实验基础和理论依据。

类风湿关节炎（RA）是一种以残毁性关节炎为主要特征的自身免疫病，破骨细胞活化在RA关节破坏中起主要作用，而滑膜细胞RANKL分泌增加是破骨细胞分化的必要条件。IL-22通过诱导JAK-2/STAT-3和p38 MAPK/NF-κB信号转导通路的活化促进了RANKL的大量表达。我们的前期研究发现1,25(OH)2D3参与了RA的免疫反应并与关节炎症有关。同时，1,25(OH)2D3可降低RA患者血清IL-22的水平，并呈剂量依赖性的抑制RANKL表达，从而延缓骨破坏。本研究以RA患者成纤维滑膜细胞为研究对象，实验证实1,25(OH)2D3可以通过阻断上述信号转导途径抑制RA患者滑膜细胞RANKL的表达，影响破骨细胞的形成，实现对RA患者的骨保护效应，为临床使用1,25(OH)2D3提供实验基础和理论依据。