Pitavastatin enhanced BMP-2 and osteocalcin expression by inhibition of Rho-associated kinase in human osteoblasts.
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.
Ohnaka
K
K
Department of Geriatric Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. oonaka@geriat.med.kyushu-u.ac.jp
Shimoda
S
S
Nawata
H
H
Shimokawa
H
H
Kaibuchi
K
K
Iwamoto
Y
Y
Takayanagi
R
R
D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000096:biosynthesis / Q000235:genetics*; D002478:Cells, Cultured; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins; D010006:Osteoblasts / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D015675:Osteocalcin / Q000096:biosynthesis / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011804:Quinolines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D016212:Transforming Growth Factor beta; D054460:rho-Associated Kinases
C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D011804:Quinolines; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D015675:Osteocalcin; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; C108475:pitavastatin