Continuous Inhibition of MAPK Signaling Promotes the Early Osteoblastic Differentiation and Mineralization of the Extracellular Matrix

Higuchi, Chikahisa; Myoui, Akira; Hashimoto, Nobuyuki; Kuriyama, Kenji; Yoshioka, Kiyoko; Yoshikawa, Hideki; Itoh, Kazuyuki

doi:10.1359/jbmr.2002.17.10.1785

Cited by 159 publications

(132 citation statements)

References 37 publications

(58 reference statements)

Supporting

Mentioning

120

Contrasting

Order By: Relevance

“…Only estrogen showed high-density bone without changing the ossicle size. We also recently reported the inhibitors for MEK (MAP kinase kinase)-enhanced osteogenesis (ALP activity, osteocalcin secretion, and nodule formation) in the culture cells [6]. However, we could not check the effect of MEK inhibitor on the in vivo BMP-induced osteogenesis because of the limiting availability of the compound.…”

Section: Discussionmentioning

confidence: 87%

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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 87%

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

Self Cite

View full text Add to dashboard Cite

show abstract

“…However, this inhibition may have some positive consequences since inhibition of early osteoblast proliferation may lead to enhanced differentiation as the cells mature (Owen et al 1990a). This is supported by the finding that continuous inhibition of MAP kinase signaling promotes early osteoblastic differentiation and mineralization (Higuchi et al 2002), and by reports that DHT treatment can enhance osteoblast differentiation. Positive effects of androgen treatment on osteoblast differentiation and matrix production include increases in alkaline phosphatase activity and mRNA expression, and type I -1 collagen protein and mRNA levels (Benz et al 1991, Gray et al 1992, and effects on mineral accumulation (Kapur & Reddi 1989, Takeuchi et al 1994.…”

Section: Discussionmentioning

confidence: 90%

Androgen inhibition of MAP kinase pathway and Elk-1 activation in proliferating osteoblasts

Wiren¹,

Toombs²,

Xw³

2004

Journal of Molecular Endocrinology

View full text Add to dashboard Cite

Non-aromatizable androgens have significant beneficial effects on skeletal homeostasis independently of conversion to estradiol, but the effects of androgens on bone cell metabolism and cell proliferation are still poorly understood. Using an osteoblastic model with enhanced androgen responsiveness, MC3T3-E1 cells stably transfected with androgen receptor (AR) under the control of the type I collagen promoter (colAR-MC3T3), the effects of androgens on mitogenic signaling were characterized. Cultures were treated with the non-aromatizable androgen 5 -dihydrotestosterone (DHT) and the effects on osteoblast viability were determined as measured by an MTT assay. A complex response was observed in that continuous short-term DHT treatment enhanced osteoblast viability, but with longer-term DHT treatment inhibition was observed. The inhibition by DHT was prevented by the specific AR antagonist hydroxyflutamide, and was also observed in primary cultures of normal rat calvarial osteoblasts. In order to identify potential mediators of this effect, mitogenic pathway-specific cDNA microarrays were interrogated. Reduced hybridization of several genes important in MAP kinase-mediated signaling was observed, with the most dramatic effect on Elk-1 expression. Analysis of phosphorylation cascades demonstrated that DHT treatment inhibited phosphoERK1/2 levels, MAP kinase activation of Elk-1, Elk-1 protein and phosphoElk-1 levels, and downstream AP-1/luciferase reporter activity. Together, these data provide the first evidence that androgen inhibition of the MAP kinase signaling pathway is a potential mediator of osteoblast growth, and are consistent with the hypothesis that the MAP cascade may be a specific downstream target of DHT.

show abstract

“…Both OPN and OC are recognized as markers of late stage of osteoblastic differentiation (33,37). In addition to the analyses of these 4 markers, we also examined the level of mineralization.…”

Section: Discussionmentioning

confidence: 99%

Coleusin Factor, a Novel Anticancer Diterpenoid, Inhibits Osteosarcoma Growth by Inducing Bone Morphogenetic Protein-2–Dependent Differentiation

Geng

Sun

et al. 2014

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Coleusin factor is a diterpenoid compound isolated from the root of a tropical plant, Coleus forskohlii. Although Coleusin factor has been reported to suppress proliferation of and induce apoptosis in several types of cancer cells, the effects of Coleusin factor on osteosarcoma and the underlying mechanism are still not fully understood. In this study, we show that Coleusin factor treatment potently inhibits the growth of osteosarcoma cells associated with G 1 cell-cycle arrest. Interestingly, apoptosis and cell death are not induced. Instead, Coleusin factor causes osteosarcoma cells to exhibit typical properties of differentiated osteoblasts, including a morphologic alteration resembling osteoblasts, the expression of osteoblast differentiation markers, elevated alkaline phosphatase activity, and increased cellular mineralization. Coleusin factor treatment significantly increases the expression of bone morphogenetic protein-2 (BMP-2), a crucial osteogenic regulator, and runt-related transcription factor 2 (RUNX2), one of the key transcription factors of the BMP pathway. When BMP-2 signaling is blocked, Coleusin factor fails to inhibit cell proliferation and to induce osteoblast differentiation. Thus, upregulation of BMP-2 autocrine is critical for Coleusin factor to induce osteoblast differentiation and exert its anticancer effects on osteosarcoma. Importantly, administration of Coleusin factor inhibits the growth of osteosarcoma xenografted in nude mice without systemic or immunologic toxicity. Osteosarcoma is a highly aggressive cancer marked by the loss of normal differentiation. Coleusin factor represents a new type of BMP-2 inducer that restores differentiation in osteosarcoma cells. It may provide a promising therapeutic strategy against osteosarcoma with minimal side effects. Mol Cancer Ther; 13(6);

show abstract

Continuous Inhibition of MAPK Signaling Promotes the Early Osteoblastic Differentiation and Mineralization of the Extracellular Matrix

Abstract: We screened the small molecule compounds that stimulate osteogenesis by themselves or promote bone morphogenetic protein (BMP)-induced bone formation. We found that a specific inhibitor for MAPK/ extracellular signal-regulated kinase kinase (

Cited by 159 publications

References 37 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

Androgen inhibition of MAP kinase pathway and Elk-1 activation in proliferating osteoblasts

Coleusin Factor, a Novel Anticancer Diterpenoid, Inhibits Osteosarcoma Growth by Inducing Bone Morphogenetic Protein-2–Dependent Differentiation

Contact Info

Product

Resources

About