Beta-catenin and BMP-2 synergize to promote osteoblast differentiation and new bone formation.
Mutations of critical components of the Wnt pathway profoundly affect skeletal development and maintenance, probably via modulation of beta-catenin signaling. We tested the hypothesis that beta-catenin is involved in mesenchymal lineage allocation to osteogenic cells using a beta-catenin mutant with constitutive transcriptional activity (DeltaN151). Although this stable beta-catenin had no effects by itself on osteogenic differentiation of multipotent embryonic cell lines, it synergized with bone morphogenetic protein-2 (BMP-2) resulting in dramatic stimulation of alkaline phosphatase activity, osteocalcin gene expression, and matrix mineralization. Likewise, DeltaN151 and BMP-2 synergistically stimulated new bone formation after subperiosteal injection in mouse calvaria in vivo. Conversely, DeltaN151 prevented adipogenic differentiation from pre-adipocytic or uncommitted mesenchymal cells in vitro. Intriguingly, the synergism with BMP-2 on gene transcription occurred without altering expression of Cbfa1/Runx2, suggesting actions independent or downstream of this osteoblast-specific transcription factor. Thus, beta-catenin directs osteogenic lineage allocation by enhancing mesenchymal cell responsiveness to osteogenic factors, such as BMP-2, in part via Tcf/Lef dependent mechanisms. In vivo, this synergism leads to increased new bone formation.
Mbalaviele
Gabriel
G
Division of Bone and Mineral Diseases, Department of Internal Medicine, St. Louis, Missouri 63110, USA.
Sheikh
Sharmin
S
Stains
Joseph P
JP
Salazar
Valerie S
VS
Cheng
Su-Li
SL
Chen
Di
D
Civitelli
Roberto
R
D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002454:Cell Differentiation; D019070:Cell Lineage; D050659:Core Binding Factor Alpha 1 Subunit; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004357:Drug Synergism; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D051821:Lymphoid Enhancer-Binding Factor 1; D008648:Mesoderm / Q000166:cytology / Q000378:metabolism; D051379:Mice; D009154:Mutation / Q000235:genetics; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D015675:Osteocalcin / Q000378:metabolism; D010012:Osteogenesis / Q000502:physiology*; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D050656:Transcription Factor AP-2; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D051176:beta Catenin
C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; C495267:CTNNB1 protein, mouse; D050659:Core Binding Factor Alpha 1 Subunit; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D051821:Lymphoid Enhancer-Binding Factor 1; C493716:Runx2 protein, mouse; D015534:Trans-Activators; D050656:Transcription Factor AP-2; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D051176:beta Catenin; D015675:Osteocalcin; D000469:Alkaline Phosphatase