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101.
David Fong Martine Bisson Gino Laberge Stephen McManus Guillaume Grenier Nathalie Faucheux Sophie Roux 《Cellular signalling》2013,25(4):717-728
BMP-9 is a potent osteogenic factor; however, its effects on osteoclasts, the bone-resorbing cells, remain unknown. To determine the effects of BMP-9 on osteoclast formation, activity and survival, we used human cord blood monocytes as osteoclast precursors that form multinucleated osteoclasts in the presence of RANKL and M-CSF in long-term cultures. BMP-9 did not affect osteoclast formation, but adding BMP-9 at the end of the culture period significantly increased bone resorption compared to untreated cultures, and reduced both the rate of apoptosis and caspase-9 activity. BMP-9 also significantly downregulated the expression of pro-apoptotic Bid, but only after RANKL and M-CSF, which are both osteoclast survival factors, had been eliminated from the culture medium. To investigate the mechanisms involved in the effects of BMP-9, we first showed that osteoclasts expressed some BMP receptors, including BMPR-IA, BMPR-IB, ALK1, and BMPR-II. We also found that BMP-9 was able to induce the phosphorylation of Smad-1/5/8 and ERK 1/2 proteins, but did not induce p38 phosphorylation. Finally, knocking down the BMPR-II receptor abrogated the BMP-9-induced ERK-signaling, as well as the increase in bone resorption. In conclusion, these results show for the first time that BMP-9 directly affects human osteoclasts, enhancing bone resorption and protecting osteoclasts against apoptosis. BMP-9 signaling in human osteoclasts involves the canonical Smad-1/5/8 pathway, and the ERK pathway. 相似文献
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Sébastien Besseau Franziska Kellner Arnaud Lanoue Antje M.K. Thamm Vonny Salim Bernd Schneider Fernando Geu-Flores René H?fer Grégory Guirimand Anthony Guihur Audrey Oudin Ga?lle Glevarec Emilien Foureau Nicolas Papon Marc Clastre Nathalie Giglioli-Guivarc’h Benoit St-Pierre Danièle Werck-Reichhart Vincent Burlat Vincenzo De Luca Sarah E. O’Connor Vincent Courdavault 《Plant physiology》2013,163(4):1792-1803
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Jean‐Noël Octave Nathalie Pierrot Susana Ferao Santos Natalia N. Nalivaeva Anthony J. Turner 《Journal of neurochemistry》2013,126(2):183-190
Despite intensive studies of the secretase‐mediated processing of the amyloid precursor protein (APP) to form the amyloid β‐peptide (Aβ), in relation to Alzheimer's disease (AD), no new therapeutic agents have reached the clinics based on reducing Aβ levels through the use of secretase inhibitors or immunotherapy. Furthermore, the normal neuronal functions of APP and its various metabolites still remain under‐investigated and unclear. Here, we highlight emerging areas of APP function that may provide new insights into synaptic development, cognition, and gene regulation. By modulating expression levels of endogenous APP in primary cortical neurons, the frequency and amplitude of calcium oscillations is modified, implying a key role for APP in maintaining neuronal calcium homeostasis essential for synaptic transmission. Disruption of this homeostatic mechanism predisposes to aging and AD. Synaptic spine loss is a feature of neurogeneration resulting in learning and memory deficits, and emerging evidence indicates a role for APP, probably mediated via one or more of its metabolites, in spine structure and functions. The intracellular domain of APP (AICD) has also emerged as a key epigenetic regulator of gene expression controlling a diverse range of genes, including APP itself, the amyloid‐degrading enzyme neprilysin, and aquaporin‐1. A fuller understanding of the physiological and pathological actions of APP and its metabolic network could provide new opportunities for therapeutic intervention in AD. 相似文献
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Jimmy Stalin Karim Harhouri Lucas Hubert Caroline Subrini Daniel Lafitte Jean-Claude Lissitzky Nadia Elganfoud Stéphane Robert Alexandrine Foucault-Bertaud Elise Kaspi Florence Sabatier Michel Aurrand-Lions Nathalie Bardin Lars Holmgren Fran?oise Dignat-George Marcel Blot-Chabaud 《The Journal of biological chemistry》2013,288(13):8991-9000
The melanoma cell adhesion molecule (CD146) contains a circulating proteolytic variant (sCD146), which is involved in inflammation and angiogenesis. Its circulating level is modulated in different pathologies, but its intracellular transduction pathways are still largely unknown. Using peptide pulldown and mass spectrometry, we identified angiomotin as a sCD146-associated protein in endothelial progenitor cells (EPC). Interaction between angiomotin and sCD146 was confirmed by enzyme-linked immunosorbent assay (ELISA), homogeneous time-resolved fluorescence, and binding of sCD146 on both immobilized recombinant angiomotin and angiomotin-transfected cells. Silencing angiomotin in EPC inhibited sCD146 angiogenic effects, i.e. EPC migration, proliferation, and capacity to form capillary-like structures in Matrigel. In addition, sCD146 effects were inhibited by the angiomotin inhibitor angiostatin and competition with recombinant angiomotin. Finally, binding of sCD146 on angiomotin triggered the activation of several transduction pathways that were identified by antibody array. These results delineate a novel signaling pathway where sCD146 binds to angiomotin to stimulate a proangiogenic response. This result is important to find novel target cells of sCD146 and for the development of therapeutic strategies based on EPC in the treatment of ischemic diseases. 相似文献