Department of Oral Molecular Biology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Cell Biochem Funct. 2013 Dec;31(8):652-9. doi: 10.1002/cbf.2951. Epub 2013 Jan 22.
Simvastatin suppresses myoblast differentiation via inhibition of Rac GTPase, which is involved in the mevalonic acid pathway that produces cholesterol. Statins also inhibit adipogenic differentiation and receptor activator of NFκB ligand (RANKL) expression, possibly through the mevalonic acid pathway, although the involvement of that pathway and effector proteins in these cellular events has not been fully clarified. In the present study, we aimed to elucidate the mechanism of the effects of simvastatin on adipogenic differentiation and calcitriol-induced RANKL expression in bone marrow stromal ST2 cells. Adipogenesis and mRNA up-regulation of peroxisome proliferator-activated receptor γ and adipocyte fatty acid-binding protein were induced by troglitazone, and those events were efficiently inhibited by simvastatin. In addition, RANKL expression induced by calcitriol was abrogated by simvastatin in ST2 cells. The inhibitory effects of simvastatin were adequately compensated by the addition of either mevalonic acid or an intermediate of the mevalonic acid pathway, geranylgeranyl pyrophosphate, but not by another intermediate, farnesyl pyrophosphate. These findings suggest that protein geranylgeranylation is related to cellular differentiation in those two directions. Furthermore, inhibitor analysis demonstrated that Rac GTPase is involved in adipogenic differentiation, whereas Rho GTPase was found to be involved in RANKL expression. Taken together, the present findings suggest that geranylgeranylation of Rho family GTPase is involved in both adipogenesis and RANKL expression of stromal cells, while Rac GTPase is involved in adipogenesis and Rho GTPase in RANKL expression.
辛伐他汀通过抑制参与产生胆固醇的甲羟戊酸途径的 Rac GTPase 来抑制成肌细胞分化。他汀类药物还抑制脂肪生成分化和核因子-κB 受体激活配体（RANKL）的表达，这可能是通过甲羟戊酸途径，尽管该途径及其在这些细胞事件中的效应蛋白的参与尚未完全阐明。在本研究中，我们旨在阐明辛伐他汀对骨髓基质 ST2 细胞脂肪生成分化和钙三醇诱导的 RANKL 表达的影响机制。过氧化物酶体增殖物激活受体γ和脂肪细胞脂肪酸结合蛋白的mRNA 上调由曲格列酮诱导，并且这些事件被辛伐他汀有效抑制。此外，辛伐他汀还可阻断钙三醇诱导的 ST2 细胞中 RANKL 的表达。在添加甲羟戊酸或甲羟戊酸途径的中间产物香叶基香叶基焦磷酸后，辛伐他汀的抑制作用得到充分补偿，但添加另一种中间产物法尼基焦磷酸则不能补偿。这些发现表明，蛋白质香叶基化与这两个方向的细胞分化有关。此外，抑制剂分析表明 Rac GTPase 参与脂肪生成分化，而 Rho GTPase 则参与 RANKL 表达。综上所述，本研究结果表明，Rho 家族 GTPase 的香叶基化参与了基质细胞的脂肪生成和 RANKL 表达，而 Rac GTPase 参与了脂肪生成，Rho GTPase 则参与了 RANKL 的表达。
