title: Bone morphogenetic protein-9 activates Smad and ERK pathways and supports human osteoclast function and survival in vitro.
abstract: 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.
authors: Division of Rheumatology, Faculty of Medicine, University of Sherbrooke, 3001, 12th Avenue North, Sherbrooke, Quebec, Canada.
authors: David
authors: D
authors: Fong
authors: Martine
authors: M
authors: Bisson
authors: Gino
authors: G
authors: Laberge
authors: Stephen
authors: S
authors: McManus
authors: Guillaume
authors: G
authors: Grenier
authors: Nathalie
authors: N
authors: Faucheux
authors: Sophie
authors: S
authors: Roux
mesh_terms: D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D001862:Bone Resorption; D053181:Caspase 8 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005312:Fetal Blood / Q000166:cytology; D055427:Growth Differentiation Factor 2 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D053245:RANK Ligand / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D051785:Smad Proteins / Q000378:metabolism*
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; D055427:Growth Differentiation Factor 2; D053245:RANK Ligand; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D051785:Smad Proteins; D016173:Macrophage Colony-Stimulating Factor; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D052006:Bone Morphogenetic Protein Receptors, Type II; D053181:Caspase 8; D053453:Caspase 9