title: BMP3 suppresses osteoblast differentiation of bone marrow stromal cells via interaction with Acvr2b.
abstract: Enhancing bone morphogenetic protein (BMP) signaling increases bone formation in a variety of settings that target bone repair. However, the role of BMP in the maintenance of adult bone mass is not well understood. Targeted disruption of BMP3 in mice results in increased trabecular bone formation, whereas transgenic overexpression of BMP3 in skeletal cells leads to spontaneous fracture, consistent with BMP3 having a negative role in bone mass regulation. Here we investigate the importance of BMP3 as a mediator of BMP signaling in the adult skeleton. We find that osteoblasts (OBL) and osteocytes are the source of BMP3 in adult bone. Using in vitro cultures of primary bone marrow stromal cells, we show that overexpression of BMP3 suppresses OBL differentiation, whereas loss of BMP3 increases colony-forming unit fibroblasts and colony-forming unit OBL. The ability of BMP3 to affect OBL differentiation is due to its interaction with activin receptor type 2b (Acvr2b) because knockdown of endogenous Acvr2b in bone marrow stromal cells reduces the suppressive effect of BMP3 on OBL differentiation. These findings best fit a model in which BMP3, produced by mature bone cells, acts to reduce BMP signaling through Acvr2b in skeletal progenitor cells, limiting their differentiation to mature OBL. Our data further support the idea that endogenous BMPs have a physiological role in regulating adult bone mass.
authors.affiliation: Department of Developmental Biology, Harvard School of Dental Medicine, Boston, Massachusetts 02115, USA.
authors.forename: Shoichiro
authors.initials: S
authors.lastname: Kokabu
authors.forename: Laura
authors.initials: L
authors.lastname: Gamer
authors.forename: Karen
authors.initials: K
authors.lastname: Cox
authors.forename: Jonathan
authors.initials: J
authors.lastname: Lowery
authors.forename: Kunikazu
authors.initials: K
authors.lastname: Tsuji
authors.forename: Regina
authors.initials: R
authors.lastname: Raz
authors.forename: Aris
authors.initials: A
authors.lastname: Economides
authors.forename: Takenobu
authors.initials: T
authors.lastname: Katagiri
authors.forename: Vicki
authors.initials: V
authors.lastname: Rosen
mesh_terms: D030301:Activin Receptors, Type II / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism*; D055398:Bone Morphogenetic Protein 3 / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D002460:Cell Line; D055879:Gene Knock-In Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D010011:Osteocytes / Q000166:cytology / Q000378:metabolism; D010012:Osteogenesis; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism*
chemical_list: C525758:Bmp3 protein, mouse; D055398:Bone Morphogenetic Protein 3; D034741:RNA, Small Interfering; D051785:Smad Proteins; D030301:Activin Receptors, Type II; C425584:activin receptor type II-B
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