Kim Jeong Yeon, Lee Eun Young, Lee Eun Bong, Lee Yun Jong, Yoo Hyun Jung, Choi Jiyong, Song Yeong Wook
Arthritis Res Ther. 2012 Aug 17;14(4):R187. doi: 10.1186/ar4018.
Statins, hydroxymethylglutaryl-coenzyme A reductase inhibitors, have been reported to have antiinflammatory and/or immunomodulatory effects and prophylactic and therapeutic effects in collagen-induced arthritis, an experimental model of rheumatoid arthritis (RA). The authors undertook to determine the effect of atorvastatin on the expressions of osteoprotegerin (OPG) and receptor activator of nuclear factor κB ligand (RANKL) in RA fibroblast-like synoviocytes (FLSs), to identify the mechanisms responsible for these effects, and to determine whether the statin inhibits osteoclastogenesis.
FLSs isolated from five RA patients were cultured in the presence of 20 ng/ml of tumor necrosis factor-α (TNF-α) with or without atorvastatin. RANKL expressions were assayed with Western blotting and enzyme-linked immunosorbent assay. RANKL, RANK, and OPG expression were assayed with reverse transcription-polymerase chain reaction (RT-PCR). Osteoclast formation was assayed by counting cells after staining for tartrate-resistant acid phosphatase in cocultures of peripheral blood mononuclear cells (PBMCs) and RA FLSs.
Atorvastatin inhibited the expression of RANKL in RA FLSs in a dose-dependent manner, and the suppression of RANKL was prevented by mevalonate. However, OPG expression was not affected by atorvastatin in RA FLSs, and atorvastatin did not affect RANK expression in CD14⁺ cells. Conversely, atorvastatin suppressed TNF-α-induced p38 phosphorylation in RA FLSs and significantly reduced TRAP-positive multinucleated osteoclast formation in the coculture of PBMCs and RA FLSs.
These results suggest that atorvastatin inhibits osteoclastogenesis and bone destruction in RA patients.
他汀类药物，即羟甲基戊二酰辅酶A还原酶抑制剂，据报道在胶原诱导的关节炎（类风湿性关节炎（RA）的一种实验模型）中具有抗炎和/或免疫调节作用以及预防和治疗作用。作者旨在确定阿托伐他汀对RA成纤维细胞样滑膜细胞（FLS）中骨保护素（OPG）和核因子κB受体活化因子配体（RANKL）表达的影响，以确定这些作用的机制，并确定他汀类药物是否抑制破骨细胞生成。
从5例RA患者中分离出的FLS在含有或不含有阿托伐他汀的20 ng/ml肿瘤坏死因子-α（TNF-α）存在下培养。用蛋白质印迹法和酶联免疫吸附测定法检测RANKL表达。用逆转录-聚合酶链反应（RT-PCR）检测RANKL、RANK和OPG表达。通过对外周血单核细胞（PBMC）和RA FLS共培养物中抗酒石酸酸性磷酸酶染色后的细胞计数来检测破骨细胞形成。
阿托伐他汀以剂量依赖性方式抑制RA FLS中RANKL的表达，甲羟戊酸可阻止RANKL的抑制。然而，阿托伐他汀对RA FLS中OPG表达没有影响，且阿托伐他汀对CD14⁺细胞中RANK表达没有影响。相反，阿托伐他汀抑制RA FLS中TNF-α诱导的p38磷酸化，并显著减少PBMC和RA FLS共培养物中抗酒石酸酸性磷酸酶阳性多核破骨细胞的形成。
这些结果表明阿托伐他汀可抑制RA患者的破骨细胞生成和骨破坏。
