Bisphosphonate- and statin-induced enhancement of OPG expression and inhibition of CD9, M-CSF, and RANKL expressions via inhibition of the Ras/MEK/ERK pathway and activation of p38MAPK in mouse bone marrow stromal cell line ST2

Masanobu Tsubaki; Takao Satou; Tatsuki Itoh; Motohiro Imano; Masashi Yanae; Chisato Kato; Risa Takagoshi; Makiko Komai; Shozo Nishida

doi:10.1016/j.mce.2012.05.002

Bisphosphonate- and statin-induced enhancement of OPG expression and inhibition of CD9, M-CSF, and RANKL expressions via inhibition of the Ras/MEK/ERK pathway and activation of p38MAPK in mouse bone marrow stromal cell line ST2

Mol Cell Endocrinol. 2012 Sep 25;361(1-2):219-31. doi: 10.1016/j.mce.2012.05.002. Epub 2012 May 10.

Authors

Masanobu Tsubaki¹, Takao Satou, Tatsuki Itoh, Motohiro Imano, Masashi Yanae, Chisato Kato, Risa Takagoshi, Makiko Komai, Shozo Nishida

Affiliation

¹ Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashi-Osaka, Japan.

PMID: 22579611
DOI: 10.1016/j.mce.2012.05.002

Abstract

Osteoclast differentiation is influenced by receptor activator of the NF-κB ligand (RANKL), macrophage colony-stimulating factor (M-CSF), and CD9, which are expressed on bone marrow stromal cells and osteoblasts. In addition, osteoprotegerin (OPG) is known as an osteoclastogenesis inhibitory factor. In this study, we investigated whether bisphosphonates and statins increase OPG expression and inhibit the expression of CD9, M-CSF, and RANKL in the bone marrow-derived stromal cell line ST2. We found that bisphosphonates and statins enhanced OPG mRNA expression and inhibited the expression of CD9, M-CSF, and RANKL mRNA. Futhermore, bisphosphonates and statins decreased the membrane localization of Ras and phosphorylated ERK1/2, and activated the p38MAPK. This indicates that bisphosphonates and statins enhanced OPG expression, and inhibited the expression of CD9, M-CSF, and RANKL through blocking the Ras/ERK pathway and activating p38MAPK. Accordingly, we believe that its clinical applications will be investigated in the future for the development of osteoporosis therapy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Bone Marrow Cells / drug effects
Bone Marrow Cells / enzymology*
Cell Death / drug effects
Cell Line
Cell Membrane / drug effects
Cell Membrane / metabolism
Cytoplasm / drug effects
Cytoplasm / metabolism
Diphosphonates / pharmacology*
Enzyme Activation / drug effects
Gene Expression Regulation / drug effects
Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
MAP Kinase Signaling System / drug effects
Macrophage Colony-Stimulating Factor / genetics
Macrophage Colony-Stimulating Factor / metabolism*
Mice
Osteoprotegerin / genetics
Osteoprotegerin / metabolism*
Phosphorylation / drug effects
Protein Kinase Inhibitors / pharmacology
Protein Prenylation / drug effects
RANK Ligand / metabolism*
RNA, Messenger / genetics
RNA, Messenger / metabolism
Stromal Cells / drug effects
Stromal Cells / enzymology
Tetraspanin 29 / genetics
Tetraspanin 29 / metabolism*
p38 Mitogen-Activated Protein Kinases / metabolism
ras Proteins / antagonists & inhibitors
ras Proteins / metabolism
rho GTP-Binding Proteins / metabolism

Substances

Diphosphonates
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Osteoprotegerin
Protein Kinase Inhibitors
RANK Ligand
RNA, Messenger
Tetraspanin 29
Macrophage Colony-Stimulating Factor
p38 Mitogen-Activated Protein Kinases
ras Proteins
rho GTP-Binding Proteins