BMP-3 promotes mesenchymal stem cell proliferation through the TGF-beta/activin signaling pathway.
Adipogenesis plays a key role in the pathogenesis of obesity. It begins with the commitment of mesenchymal stem cells (MSCs) to the adipocyte lineage, followed by terminal differentiation of preadipocytes to mature adipocytes. A critical, but poorly understood, component of adipogenesis involves proliferation of MSCs and preadipocytes. The present study was undertaken to examine the hypothesis that bone morphogenetic protein-3 (BMP-3) promotes adipogenesis using C3H10T1/2 MSCs and 3T3-L1 preadipocytes as in vitro model systems. We demonstrated that although it did not promote the commitment of MSCs to the adipocyte lineage or the differentiation of preadipocytes to adipocytes, BMP-3-stimulated proliferation by threefold in both cell types. Owing to a lack of information on MSC proliferation, we then delineated the molecular mechanisms underlying BMP-3-stimulated MSC proliferation. We showed that BMP-3 activated the transforming growth factor-beta (TGF-beta)/activin but not ERK1/2, p38 MAPK, or JNK signaling pathways in C3H10T1/2 cells. Furthermore, the TGF-beta/activin receptor kinase inhibitor SB-431542 blocked BMP-3-stimulated proliferation. Importantly, siRNA-mediated knockdown of the key TGF-beta/activin signaling pathway components, ActRIIB, ALK4, or Smad2, abrogated the mitogenic effects of BMP-3 on MSCs. Together, these results demonstrate that BMP-3 stimulates MSC proliferation via the TGF-beta/activin signaling pathway, thus revealing a novel role for this divergent and poorly understood member of the TGF-beta superfamily in regulating MSC proliferation.
Department of Obstetrics and Gynaecology, The University of Western Ontario, Children's Health Research Institute-Lawson Health Research Institute, London, Ontario, Canada.
Aaron
A
Stewart
Haiyan
H
Guan
Kaiping
K
Yang
D041721:3T3-L1 Cells; D028341:Activins / Q000378:metabolism*; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D055398:Bone Morphogenetic Protein 3 / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D019070:Cell Lineage / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004149:Dioxoles / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects*; D051899:Smad2 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D001549:Benzamides; D055398:Bone Morphogenetic Protein 3; D004149:Dioxoles; D034741:RNA, Small Interfering; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D016212:Transforming Growth Factor beta; D028341:Activins; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases