肥胖加劇關節炎病情：作用機轉探討及未來發展臨床醫療方針的可能性

Abstract

類風溼性關節炎是一種由多種細胞(包含巨噬細胞, 關節滑膜細胞,內皮細胞, 其他免疫細胞)共同調控的系統性疾病。發炎的缺氧環境會活化類風溼性關節炎滑液細胞(RASF)，分泌出多種cytokine和 matrix metalloproteinase，造成更嚴重的發炎和周邊組織的破壞分解。類風溼性關節炎也是心血管疾病的危險因子。在病患的關節滑液中發現與atheroma有類似的細胞組成。OxLDL和27-hydroxycholesterol會加劇粥狀動脈硬化。本實驗希望探討巨噬細胞在模擬關節炎缺氧環境下對 sterol 27-hydroxylase (CYP27A1)的調控，SIRT5在巨噬細胞的變化，RASF是否會受到27-hydroxycholesterol的影響。實驗結果發現，在MonoMac 6細胞在受到缺氧刺激下，iNOS和COX-2的蛋白表現上升，CYP27A1的蛋白表現量下降。在SIRT5 overexpressed MonoMac 6細胞CYP27A1會上升。受缺氧刺激時發現，iNOS和COX-2沒有明顯變化，CYP27A1的蛋白表現量下降。27HC會促進RASF細胞的增生；但會造成U2OS細胞存活率下降。在合併缺氧與27HC刺激下，RASF分泌CCL20的量會上升。U2OS細胞分泌CCL20的量沒有明顯差異。總結上述的發現，缺氧刺激會使巨噬細胞產生與發炎相關的酵素，CYP27A1下降，可能影響正常膽固醇排出的機制。低劑量的27HC會促使RASF增生但不利骨細胞的生長。27HC也會使RASF分泌更多CCL20，造成chemotaxis。

Rheumatoid arthritis is a systemic disease regulated by different cells including macrophage, synovial fibroblast, endothelial cell and other immune cells. Inflammation related hypoxia activates rheumatoid arthritis fibroblast (RASF), resulting in cytokines and matrix metalloproteinase secretion that cause persistent chronic inflammation and destruction of surrounding tissues. Rheumatoid arthritis is one of the risk factor of cardiovascular disease. Cells extracted from synovial fluid of RA patient revealed similar composition with atherosclerosis. OxLDL and 27-hydroxycholesterol deteriorate atherosclerosis. The purpose of this study is to investigate how sterol 27-hydroxylase(CYP27A1) and sirtuin5(SIRT5) regulate macrophage metabolism under hypoxia. And the relationship of 27HC and RASF. In this study, expression of iNOS and COX-2 increased while CYP27A1 and SIRT5 decreased in MonoMac 6 cell under hypoxia Expression of CYP27A1 increased in SIRT5 overexpressed MonoMac 6 cell. No significant differences of iNOS and COX-2 expression in SIRT5 overexpressed MonoMac 6 copared under hypoxia compared to normxia whereas CYP27A1 decreased and SIRT5 expression increased.27HC promoted RASF proliferation but promoted U2OS cell death. Expression of CCL20 increased in RASF under 27HC and hypoxia while there was no significant differences in U2OS cell. In summary, macrophage secreted proinflammatory related enzyme and decreased CYP27Al level under hypoxia that might related to impared cholesterol efflux mechanism.Low-dosed 27HC might promote RASF proliferation and CCL20 expression.