Pitavastatin enhanced BMP-2 and osteocalcin expression by inhibition of Rho-associated kinase in human osteoblasts
Pitavastatin enhanced BMP-2 and osteocalcin expression by inhibition of Rho-associated kinase in human osteoblasts
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DOI：
10.1006/bbrc.2001.5597
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发表时间：
2001-09-21
影响因子：
3.1
通讯作者：
Takayanagi, R
中科院分区：
文献类型：
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作者：
Ohnaka, K;Shimoda, S;Takayanagi, R
为了阐明3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂（他汀类药物）促进骨形成的机制，我们研究了新开发的他汀类药物匹伐他汀（pitavastatin）对原代培养的人成骨细胞骨形态发生蛋白-2（BMP-2）和骨钙素表达的影响。匹伐他汀可增加BMP-2 mRNA的表达水平，更有效地增加骨钙素mRNA的表达。这种刺激作用被废除的香叶基香叶基焦磷酸，一个必不可少的分子，异戊二烯化的小GTP结合蛋白，如Rho GTdR，但不是由一氧化氮合酶和各种蛋白激酶的抑制剂。匹伐他汀抑制Rho相关激酶（Rho激酶）活性。Rho激酶的特异性抑制剂羟基法舒地尔可增加BMP-2和骨钙素的表达。这些mRNA水平被地塞米松强烈抑制，但通过与羟基法舒地尔共同治疗恢复。这些观察结果表明，Rho激酶负性调节骨形成，抑制Rho和Rho激酶途径是他汀类药物对骨作用的主要机制。此外，Rho激酶抑制剂可能是用于治疗骨质疏松症如糖皮质激素诱导的骨质疏松症的新的治疗试剂。(C)北京：科学出版社.
To clarify the mechanism of the stimulatory effect of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) on bone formation, we investigated the effect of pitavastatin, a newly developed statin, on expression of bone morphogenetic protein-2 (BMP-2) and osteocalcin in primary cultured human osteoblasts. Pitavastatin increased the expression level of mRNA for BMP-2, and much more effectively for osteocalcin. This stimulatory effect was abolished by the addition of geranylgeranyl pyrophosphate, an essential molecule for prenylation of small GTP-binding proteins such as Rho GTPase, but not by inhibitors of nitric oxide synthase and various protein kinases. Pitavastatin suppressed the Rho-associated kinase (Rho-kinase) activity. Hydroxyfasudil, a specific inhibitor of Rho-kinase, increased BMP-2 and osteocalcin expression. These mRNA levels were strongly suppressed by dexamethasone, but restored by co-treatment with hydroxyfasudil. These observations suggest that the Rho-kinase negatively regulates bone formation and the inhibition of Rho and Rho-kinase pathway is the major mechanism of the statin effect on bone. Moreover, a Rho-kinase inhibitor may be a new therapeutic reagent for the treatment of osteoporosis such as glucocorticoid-induced osteoporosis. (C) 2001 Academic Press.