Bone morphogenetic protein-3 is a negative regulator of bone density.
Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-beta (TGF-beta) superfamily. Many BMPs are produced in bone and show osteogenic activity, suggesting that they may be determinants of bone mass. BMP3 was originally purified from bone as osteogenin, which induces osteogenic differentiation. Recombinant BMP3 (rhBMP3) has no biological activity, however, leaving its role in skeletal growth unclear. Here we show that BMP3 is an antagonist of osteogenic BMPs: BMP3 dorsalizes Xenopus laevis embryos, inhibits BMP2-mediated induction of Msx2 and blocks BMP2-mediated differentiation of osteoprogenitor cells into osteoblasts. These effects appear to be mediated through activin receptors. Finally, Bmp3(-/-) mice have twice as much trabecular bone as wild-type littermates, indicating that BMP3, the most abundant BMP in adult bone, is a negative determinant of bone density.
Daluiski
A
A
Department of Orthopaedic Surgery, University of California, Los Angeles, California, USA.
Engstrand
T
T
Bahamonde
M E
ME
Gamer
L W
LW
Agius
E
E
Stevenson
S L
SL
Cox
K
K
Rosen
V
V
Lyons
K M
KM
D029404:Activin Receptors; D000818:Animals; D015519:Bone Density / Q000187:drug effects*; D055396:Bone Morphogenetic Protein 2; D055398:Bone Morphogenetic Protein 3; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000187:drug effects; D005260:Female; D005269:Femur / Q000187:drug effects / Q000378:metabolism; D018390:Gene Targeting; D055428:Growth Differentiation Factor 5; D006133:Growth Substances / Q000235:genetics; D018398:Homeodomain Proteins; D006801:Humans; D017403:In Situ Hybridization; D008297:Male; D008648:Mesoderm / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009865:Oocytes / Q000378:metabolism; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D017978:Receptors, Growth Factor / Q000378:metabolism; D011994:Recombinant Proteins; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects; D016212:Transforming Growth Factor beta; D015854:Up-Regulation / Q000187:drug effects; D014982:Xenopus laevis / Q000196:embryology
C525718:BMP2 protein, human; C525757:BMP3 protein, human; C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D055398:Bone Morphogenetic Protein 3; D019485:Bone Morphogenetic Proteins; D017077:Culture Media, Conditioned; D004268:DNA-Binding Proteins; C525893:GDF5 protein, human; C525894:Gdf5 protein, mouse; D055428:Growth Differentiation Factor 5; D006133:Growth Substances; D018398:Homeodomain Proteins; C084119:MSX2 protein; D012333:RNA, Messenger; D017978:Receptors, Growth Factor; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; C499469:recombinant human bone morphogenetic protein-2; D029404:Activin Receptors