Overexpression of developmentally regulated GTP-binding protein-2 increases bone loss.
The developmentally regulated GTP-binding protein-2 (DRG2) is a novel subclass of GTP-binding proteins. Many functional characteristics of osteoclasts (OC) are associated with small GTPases. We hypothesized that DRG2 affects bone mass via modulating OC activity. Using DRG2 transgenic mice, we investigated the role of DRG2 in bone remodeling. DRG2 overexpression caused a decrease in bone mass and an increase in the number and activity of OC in vivo. DRG2 overexpression increased fusion, spreading, survival, and resorption activity of OC in vitro. Downregulation of DRG2 by siRNA decreased fusion, spreading, and survival of OC, supporting the observations found in DRG2 transgenic OC. Transgenic mature OCs were larger, with actin rings and higher ERK, Akt, Rac1 and Rho activities than wild-type OCs. Inhibition of these proteins abolished the effects of DRG2 on formation of large OCs with actin rings, implying that DRG2 affects cytoskeleton reorganization in a Rac1/Rho/ERK/Akt-dependent manner. In summary, DRG2 is associated with survival and cytoskeleton organization of OC under influence of macrophage colony-stimulating factor, and its overexpression leads to elevated bone resorptive activity of OC, resulting in bone loss.
Department of Biological Sciences (BK21 Program) and the Immunomodulation Research Center, University of Ulsan, Ulsan, Korea.
Ke
K
Ke
Ok-Joo
OJ
Sul
Woon-Ki
WK
Kim
Mi-Hyun
MH
Lee
Myung-Seok
MS
Ko
Jae-Hee
JH
Suh
Hyun-Ju
HJ
Kim
Shin-Yoon
SY
Kim
Jeong-Woo
JW
Park
Hye-Seon
HS
Choi
D000818:Animals; D016723:Bone Remodeling / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D001862:Bone Resorption / Q000209:etiology*; D002459:Cell Fusion; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D019204:GTP-Binding Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D016173:Macrophage Colony-Stimulating Factor / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D034741:RNA, Small Interfering; C078418:developmentally regulated GTP-binding protein; D016173:Macrophage Colony-Stimulating Factor; D019204:GTP-Binding Proteins