title: 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.
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.
authors.affiliation: Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashi-Osaka, Japan.
authors.forename: Masanobu
authors.initials: M
authors.lastname: Tsubaki
authors.forename: Takao
authors.initials: T
authors.lastname: Satou
authors.forename: Tatsuki
authors.initials: T
authors.lastname: Itoh
authors.forename: Motohiro
authors.initials: M
authors.lastname: Imano
authors.forename: Masashi
authors.initials: M
authors.lastname: Yanae
authors.forename: Chisato
authors.initials: C
authors.lastname: Kato
authors.forename: Risa
authors.initials: R
authors.lastname: Takagoshi
authors.forename: Makiko
authors.initials: M
authors.lastname: Komai
authors.forename: Shozo
authors.initials: S
authors.lastname: Nishida
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000201:enzymology*; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D004164:Diphosphonates / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D053244:Osteoprotegerin / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017368:Protein Prenylation / Q000187:drug effects; D053245:RANK Ligand / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017154:Stromal Cells / Q000187:drug effects / Q000201:enzymology; D060245:Tetraspanin 29 / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D018631:ras Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism
chemical_list: D004164:Diphosphonates; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D053244:Osteoprotegerin; D047428:Protein Kinase Inhibitors; D053245:RANK Ligand; D012333:RNA, Messenger; D060245:Tetraspanin 29; D016173:Macrophage Colony-Stimulating Factor; D048051:p38 Mitogen-Activated Protein Kinases; D018631:ras Proteins; D020741:rho GTP-Binding Proteins