BMPs regulate multiple aspects of growth-plate chondrogenesis through opposing actions on FGF pathways.
Bone morphogenetic protein (BMP) signaling pathways are essential regulators of chondrogenesis. However, the roles of these pathways in vivo are not well understood. Limb-culture studies have provided a number of essential insights, including the demonstration that BMP pathways are required for chondrocyte proliferation and differentiation. However, limb-culture studies have yielded contradictory results; some studies indicate that BMPs exert stimulatory effects on differentiation, whereas others support inhibitory effects. Therefore, we characterized the skeletal phenotypes of mice lacking Bmpr1a in chondrocytes (Bmpr1a(CKO)) and Bmpr1a(CKO);Bmpr1b+/- (Bmpr1a(CKO);1b+/-) in order to test the roles of BMP pathways in the growth plate in vivo. These mice reveal requirements for BMP signaling in multiple aspects of chondrogenesis. They also demonstrate that the balance between signaling outputs from BMP and fibroblast growth factor (FGF) pathways plays a crucial role in the growth plate. These studies indicate that BMP signaling is required to promote Ihh expression, and to inhibit activation of STAT and ERK1/2 MAPK, key effectors of FGF signaling. BMP pathways inhibit FGF signaling, at least in part, by inhibiting the expression of FGFR1. These results provide a genetic in vivo demonstration that the progression of chondrocytes through the growth plate is controlled by antagonistic BMP and FGF signaling pathways.
Yoon
Byeong S
BS
Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, CA 90095, USA.
Pogue
Robert
R
Ovchinnikov
Dmitri A
DA
Yoshii
Isaac
I
Mishina
Yuji
Y
Behringer
Richard R
RR
Lyons
Karen M
KM
D000818:Animals; D017209:Apoptosis; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D049109:Cell Proliferation; D020219:Chondrogenesis / Q000235:genetics / Q000502:physiology*; D005260:Female; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D006132:Growth Plate / Q000002:abnormalities / Q000254:growth & development / Q000378:metabolism; D053823:Hedgehog Proteins; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009154:Mutation; D010009:Osteochondrodysplasias / Q000235:genetics; D010641:Phenotype; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism; D015398:Signal Transduction
D019485:Bone Morphogenetic Proteins; D053823:Hedgehog Proteins; D047908:Intracellular Signaling Peptides and Proteins; C514061:ihh protein, mouse; D005346:Fibroblast Growth Factors; C496349:Fgfr1 protein, mouse; D051496:Receptor, Fibroblast Growth Factor, Type 1; C498212:Bmpr1a protein, mouse; C498215:Bmpr1b protein, mouse; D052005:Bone Morphogenetic Protein Receptors, Type I