Although RANK-L is essential for osteoclast formation, factors such as transforming growth factor- (TGF-) are potent modulators of osteoclastogenic stimuli. To systematically investigate the role of TGF- in human osteoclastogenesis, monocytes were isolated from peripheral blood by three distinct approaches, resulting in either a lymphocyte-rich, a lymphocyte-poor, or a pure osteoclast precursor (CD14-positive) cell population. In each of these osteoclast precursor populations, the effect of TGF- on proliferation, TRAP activity, and bone resorption was investigated with respect to time and length of exposure. When using the highly pure CD14 osteoclast precursor cell population, the effect of TGF- was strongly dependent on the stage of osteoclast maturation. When monocytes were exposed to TGF- during the initial culture period (days 1-7), TRAP activity and bone resorption were increased by 40%, whereas the cell number was reduced by 25%. A similar decrease in cell number was observed when TGF- was present during the entire culture period (days 1-21), but in direct contrast, TRAP activity, cell fusion, cathepsin K, and matrix metalloproteinase (MMP)-9 expression as well as bone resorption were almost completely abrogated. Moreover, we found that latent TGF- was strongly activated by incubation with MMP-9 and suggest this to be a highly relevant mechanism for regulating osteoclast activity. To further investigate the molecular mechanism responsible for the divergent effects of continuous versus discontinuous exposure to TGF-, we examined RANK expression and p38 MAPK activation. We found the TGF- strongly induced p38 MAPK in monocytes, but not in mature osteoclasts, and that continuous exposure of TGF- to monocytes down-regulated RANK expression. The current results suggest that TGF- promotes human osteoclastogenesis in monocytes through stimulation of the p38 MAPK, whereas continuous exposure to TGF- abrogates osteoclastogenesis through down-regulation of RANK expression and therefore attenuation of RANK-RANK-L signaling.
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"Det er den unge Sartre, der er vor tids filosof, ikke den ældre", konkluderer Hans Bell-Johansen i 1994 i sin diskussion af Sartre som politisk filosof. Konklusionen søges begrundet i nogle få påstande omkring Sartres politiske stillingtagen i forhold til kommunismen, som førte til et brud med MerleauPonty, og ved en løs reference til Sartres filosofiske værk, hvorom Jacques Colettes siger: "der er intet interessant ved Sartres 'forbedring' af marxismen."
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