Pitavastatin Enhanced BMP-2 and Osteocalcin Expression by Inhibition of Rho-Associated Kinase in Human Osteoblasts

Ohnaka, Keizo; Shimoda, Seiko; Nawata, H; Shimokawa, Hiroaki; Kaibuchi, Kozo; Iwamoto, Yoshihisa; Takayanagi, Ryoichi

doi:10.1006/bbrc.2001.5717

Cited by 76 publications

(122 citation statements)

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“…If this is the case, a ROCK inhibitor might be a more promising and specific stimulator for the promoting of osteogenesis, since it exists downstream in the signal transduction cascade. Consistent with the results, Ohnaka et al [26] reported that pitavastatin, a newly developed statin, enhanced BMP-2 and osteocalcin expression in Rho-associated kinase dependent manner in primary cultured human osteoblasts. They also reported that hydroxyfasudil, a specific inhibitor for ROCK, increased BMP-2 and osteocalcin production.…”

Section: Discussionsupporting

confidence: 74%

Stimulation of Ectopic Bone Formation in Response to BMP-2 by Rho Kinase Inhibitor: A Pilot Study

Yoshikawa

Yoshioka

Nakase

et al. 2009

Clin Orthop Relat Res

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The small GTPase Rho and Rho-associated protein kinase (Rho kinase, ROCK) signal participates in a variety of biological functions including vascular contraction, tumor invasion, and penile erection. Evidence also suggests Rho-ROCK is involved in signaling for mesenchymal cellular differentiation. However, whether it is involved in osteoblastic differentiation is unknown. We therefore asked whether Rho-ROCK signaling participates in recombinant human bone morphogenetic protein (rhBMP-2)-induced osteogenesis both in vitro and in vivo. Continuous delivery of a specific ROCK inhibitor (Y-27632) enhanced ectopic bone formation induced by rhBMP-2 impregnated into an atelocollagen carrier in mice without affecting systemic bone metabolism. Treatment with Y-27632 also enhanced the osteoblastic differentiation of cultured murine neonatal calvarial cells. These effects were associated with increased expression of BMP-4 gene. Expression of a dominant negative mutant of ROCK in ST2 cells promoted osteoblastic differentiation, while a constitutively active mutant of ROCK attenuated osteoblastic differentiation and the ROCK inhibitor reversed this phenotype. Thus, ROCK inhibits osteogenesis, and a ROCK inhibitor in combination with the local delivery of rhBMP/collagen composite may be clinically applicable for stimulating bone formation.

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Section: Discussionsupporting

confidence: 74%

Stimulation of Ectopic Bone Formation in Response to BMP-2 by Rho Kinase Inhibitor: A Pilot Study

Yoshikawa

Yoshioka

Nakase

et al. 2009

Clin Orthop Relat Res

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“…Ohnaka et al (2001) have demonstrated stimulatory effects of pitavastatin on the expression of BMP-2 and osteocalcin mRNA in primary cultured human osteoblasts, in which Rho-kinase inhibition was shown as the major mechanism of statin-induced osteoblastic differentiation. Ghosh-Choudhury et al (2007) showed possible signaling crosstalk for the statin-induced osteoblast differentiation.…”

Section: Discussionmentioning

confidence: 99%

Simvastatin antagonizes tumor necrosis factor-α inhibition of bone morphogenetic proteins-2-induced osteoblast differentiation by regulating Smad signaling and Ras/Rho-mitogen-activated protein kinase pathway

Yamashita¹,

Otsuka²,

Mukai

et al. 2008

Journal of Endocrinology

108

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Recent studies have shown that the mevalonate pathway plays an important role in skeletal metabolism. Statins stimulate bone morphogenetic proteins-2 (BMP-2) production in osteoblasts, implicating a possible beneficial role for statins in promoting anabolic effects on bone. Here, we investigated the effects of a lipophilic simvastatin on osteoblast differentiation using mouse myoblast C2C12 cells, in the presence of tumor necrosis factor-a (TNF-a), an inflammatory cytokine that inhibits osteogenesis. The addition of TNF-a to C2C12 cells suppressed the BMP-2-induced expression of key osteoblastic markers including Runx2 and alkaline phosphatase (ALP) activity. Simvastatin had no independent effects on Runx2 and alkaline phosphatase activity; however, it reversed the suppressive effects of TNF-a. The ability of simvastatin to reverse TNF-a inhibition of BMP-induced Smad1,5,8 phosphorylation and Id-1 promoter activity suggests the involvement of Smad signaling pathway in simvastatin action. In addition, cDNA array analysis revealed that simvastatin increased expression levels of Smads in C2C12 cells exposed to TNF-a that also activated mitogenactivated protein kinase (MAPK) signaling pathways, including extracellular signal-regulated kinase 1/2 (ERK1/2), P38, and stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK). Simvastatin potently suppressed TNFa-induced phosphorylation of ERK1/2 and SAPK/JNK by inhibiting TNF-a-induced membrane localization of Ras and RhoA. Farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) reversed the simvastatin effects on TNF-a-induced activation of Ras/Rho/MAPK pathways. FPP and GGPP also restored the simvastatin effects on TNFa-induced suppression of Runx2 and ALP activity. In addition, simvastatin decreased the expression levels of TNF type-1 and -2 receptor mRNAs. Collectively, simvastatin supports BMP-induced osteoblast differentiation through antagonizing TNF-a-to-Ras/Rho/MAPK pathway and augmenting BMP-Smad signaling, suggesting a potential usage of statins to ameliorate inflammatory bone damage.

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“…On the other hand, we and other investigators have recently shown that fasudil could also affect bone by inducing bone morphogenetic protein-2 (BMP-2) in osteoblasts and stimulate their differentiation and mineralization [5,6]. Thus, agents inhibiting ROK are expected to be candidate drugs not only curing the cardiovascular disease but also promoting bone formation for the treatment of osteoporosis.…”

mentioning

confidence: 99%

Fasudil hydrochloride induces osteoblastic differentiation of stromal cell lines, C3H10T1/2 and ST2, via bone morphogenetic protein-2 expression

et al. 2010

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Pitavastatin Enhanced BMP-2 and Osteocalcin Expression by Inhibition of Rho-Associated Kinase in Human Osteoblasts

Cited by 76 publications

References 0 publications

Stimulation of Ectopic Bone Formation in Response to BMP-2 by Rho Kinase Inhibitor: A Pilot Study

Stimulation of Ectopic Bone Formation in Response to BMP-2 by Rho Kinase Inhibitor: A Pilot Study

Simvastatin antagonizes tumor necrosis factor-α inhibition of bone morphogenetic proteins-2-induced osteoblast differentiation by regulating Smad signaling and Ras/Rho-mitogen-activated protein kinase pathway

Fasudil hydrochloride induces osteoblastic differentiation of stromal cell lines, C3H10T1/2 and ST2, via bone morphogenetic protein-2 expression

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