Previous studies found that BMPs support osteoclast formation, but it is not clear whether this is a direct effect on osteoclasts or mediated indirectly through osteoblasts. We have shown that a mouse deficient for the BMP antagonist Twisted gastrulation suggested a direct positive role for BMPs on osteoclastogenesis. In this report, we further determine the significance of BMP signaling on osteoclast formation in vitro. We find that BMP2 synergizes with suboptimal levels of RANKL to enhance in vitro differentiation of osteoclast-like cells. The enhancement by BMP2 is not a result of changes in the rate of proliferation or survival of the bone marrow derived cultures, but is accompanied by an increase in expression of genes involved in osteoclast differentiation and fusion. Treatment with BMP2 did not significantly alter expression of RANKL or OPG in our osteoclast cultures, suggesting that the enhancement of osteoclastogenesis is not mediated indirectly through osteoblasts or stromal cells. Consistent with this, we detected phosphorylated SMAD1,5, in the nuclei of mononuclear and multinucleated cells in osteoclast cultures. Levels of p-SMAD, BMP2 and BMP receptors increased during differentiation. RNAi suppression of Type II BMP receptor inhibited RANKL-stimulated formation of multinuclear TRAP positive cells. The BMP antagonist noggin inhibited RANKL-mediated osteoclast differentiation when added prior to day 3, while addition of noggin on day 3 or later failed to inhibit their differentiation. Taken together, these data indicate that osteoclasts express BMP2 and BMP receptors, and that autocrine BMP signaling directly promotes the differentiation of osteoclasts-like cells. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptBone is a highly dynamic tissue, characterized by a continuous cycle of bone formation by osteoblasts and bone resorption by osteoclasts [Henriksen et al., 2009;Sims and Gooi, 2008]. This cycle permits physiological bone growth, repair of damaged bone, and is important for regulation of systemic calcium and phosphate levels. Dysregulation of the cycle results in numerous pathological conditions such as osteoporosis, Paget's disease, and arthritis [Rodan and Martin, 2000]. It also contributes to the progression and morbidity of osteolytic cancers such as myeloma, osteosarcoma and metastatic breast, lung and prostate tumors [Guise et al., 2006;Roodman, 2009].Osteoclasts are large, multinucleated cells formed by fusion of mononuclear cells that derive from the monocyte/macrophage lineage [Vaananen and Laitala-Leinonen, 2008]. They produce proteases and other factors to degrade the inorganic mineral and organic protein components of bone, thereby facilitating repair and remodeling [Teitelbaum, 2000]. Two factors that are necessary and sufficient for osteoclast formation are M-CSF [Cecchini et al., 1997] and Receptor Activator of NF-κB Ligand (RANKL) [Wada et al., 2006], both of which are expressed by osteoblasts. M-CSF is required for survival and proliferation of...
Background: BMPs affect osteoclastogenesis in vitro, but the effects of BMP signaling on osteoclastogenesis in vivo are not well understood. Results: Conditional deletion of BMPRII in osteoclasts results in reduced osteoclastogenesis, resulting in increased bone. Conclusion: BMP signaling is required for proper bone remodeling in vivo. Significance: Identifying factors affecting osteoclast differentiation increase understanding of bone remodeling regulation in vivo.
Histone deacetylases (HDACs) are negative regulators of transcription. Endochondral bone formation including chondrocyte and osteoblast maturation is regulated by HDACs. Very little is known about the role HDACs play in osteoclast differentiation. It has been previously reported that HDAC inhibitors, trichostatin A and sodium butyrate, suppress osteoclast differentiation through multiple mechanisms. In this study, we report that suppression of HDAC3 expression similar to HDAC inhibitors inhibits osteoclast differentiation, whereas osteoclasts suppressed for HDAC7 expression had accelerated differentiation when compared with control cells. Mitf, a transcription factor, is necessary for osteoclast differentiation. We demonstrate that Mitf and HDAC7 interact in RAW 264 cells and osteoclasts. The transcriptional activity of Mitf is repressed by HDAC7. Lastly, we show that either the amino or the carboxyl terminus of HDAC7 is sufficient for transcriptional repression and that the repression of HDAC7 is insensitive to trichostatin A, indicating that HDAC7 represses Mitf at least in part by deacetylation-independent mechanism.
We investigated the role of the alcohol environment in explaining disparities in homicide rates among minorities in 10 cities in the United States using 2003 data from the Malt Liquor and Homicide study. We hypothesized that (a) higher concentrations of African Americans would be associated with higher homicide rates, as well as higher alcohol and malt liquor availability and promotion, and (b) the relationship between neighborhood racial/ethnic concentration and homicide would be attenuated by the greater alcohol and malt liquor availability and promotion in African American neighborhoods. Hypotheses were tested using separate Poisson, linear, and logistic regression models that corrected for spatial autocorrelation. Census block groups served as the unit of analysis (n = 450). We found that higher concentrations of African Americans were associated with higher homicide rates as well as greater alcohol availability, especially malt liquor availability. The promotion of malt liquor on storefronts was also significantly greater in African American than in other neighborhoods. However, none of the measures representing alcohol or malt liquor availability and promotion variables changed the effect of neighborhood racial/ethnic concentration on homicide. Limitations and implications of our findings are discussed.
There is strong clinical evidence that implicates tenofovir in the loss of bone mineral density during treatment of human immunodeficiency virus infection. In this study, we sought to test the hypothesis that tenofovir treatment of osteoblasts causes changes in the gene expression profile that would impact osteoblast function during bone formation. Primary osteoblasts were isolated and then treated with the tenofovir prodrug, tenofovir disoproxil fumarate (TDF). Total RNA from TDF-treated and untreated osteoblasts were extracted and used for microarray analysis to assess TDF-associated changes in the gene expression profile. Strikingly, the changes in gene expression profiles involved in cell signaling, cell cycle and amino acid metabolism, which would likely impact osteoblast function in bone formation. Our findings demonstrate for the first time that tenofovir treatment of primary osteoblasts results in gene expression changes that implicate loss of osteoblast function in tenofovir-associated bone mineral density loss.
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