The developmentally regulated GTP-binding protein 2 (DRG2) is a novel subclass of GTP binding proteins. Many functional characteristics of osteoclast (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. Down-regulation 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 M-CSF, and its overexpression leads to elevated bone resorptive activity of OC, resulting in bone loss.
[Show abstract][Hide abstract] ABSTRACT: Osteoclasts are specialized cells derived from the monocyte/macrophage haematopoietic lineage that develop and adhere to bone matrix, then secrete acid and lytic enzymes that degrade it in a specialized, extracellular compartment. Discovery of the RANK signalling pathway in the osteoclast has provided insight into the mechanisms of osteoclastogenesis and activation of bone resorption, and how hormonal signals impact bone structure and mass. Further study of this pathway is providing the molecular basis for developing therapeutics to treat osteoporosis and other diseases of bone loss.
[Show abstract][Hide abstract] ABSTRACT: Osteoclasts (OCs) undergo rapid apoptosis without trophic factors, such as macrophage colony-stimulating factor (M-CSF). Their apoptosis was associated with a rapid and sustained increase in the pro-apoptotic BH3-only Bcl-2 family member Bim. This was caused by the reduced ubiquitylation and proteasomal degradation of Bim that is mediated by c-Cbl. Although the number of OCs was increased in the skeletal tissues of bim-/- mice, the mice exhibited mild osteosclerosis due to reduced bone resorption. OCs differentiated from bone marrow cells of bim-/- animals showed a marked prolongation of survival in the absence of M-CSF, compared with bim+/+ OCs, but the bone-resorbing activity of bim-/- OCs was significantly reduced. Overexpression of a degradation-resistant lysine-free Bim mutant in bim-/- cells abrogated the anti-apoptotic effect of M-CSF, while wild-type Bim did not. These results demonstrate that ubiquitylation-dependent regulation of Bim levels is critical for controlling apoptosis and activation of OCs.
The EMBO Journal 01/2004; 22(24):6653-64. DOI:10.1093/emboj/cdg635 · 10.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to investigate whether the combination of dual-energy X-ray absorptiometry (DXA)-based bone mass and magnetic resonance imaging (MRI)-based cortical and trabecular structural measures improves the prediction of radial bone strength. Thirty-eight left forearms were harvested from formalin-fixed human cadavers. Bone mineral content (BMC) and bone mineral density (BMD) of the distal radius were measured using DXA. Cortical and trabecular structural measures of the distal radius were computed in high-resolution 1.5T MR images. Cortical measures included average cortical thickness and cross-sectional area. Trabecular measures included morphometric and texture parameters. The forearms were biomechanically tested in a fall simulation to measure absolute radial bone strength (failure load). Relative radial bone strength was determined by dividing radial failure loads by age, body mass index, radius length, and average radius cross-sectional area, respectively. DXA derived BMC and BMD showed statistically significant (p < 0.05) correlations with absolute and relative radial bone strength (r ≤ 0.78). Correlation coefficients for cortical and trabecular structural measures with absolute and relative radial bone strength amounted up to r = 0.59 and r = 0.74, respectively, (p < 0.05). In combination with DXA-based bone mass, trabecular but not, cortical structural measures, added in multiple regression models significant (p < 0.05) information in predicting absolute and relative radial bone strength (up to R (adj) = 0.88). Thus, a combination of DXA-based bone mass and MRI-based trabecular structural measures most accurately predicted absolute and relative radial bone strength, whereas structural measures of the cortex did not provide significant additional information in combination with DXA.
Journal of Bone and Mineral Metabolism 11/2012; 31(2). DOI:10.1007/s00774-012-0407-8 · 2.46 Impact Factor
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