TY - JOUR
T1 - β-catenin and BMP-2 synergize to promote osteoblast differentiation and new bone formation
AU - Mbalaviele, Gabriel
AU - Sheikh, Sharmin
AU - Stains, Joseph P.
AU - Salazar, Valerie S.
AU - Cheng, Su Li
AU - Chen, Di
AU - Civitelli, Roberta
PY - 2005/2/1
Y1 - 2005/2/1
N2 - Mutations of critical components of the Wnt pathway profoundly affect skeletal development and maintenance, probably via modulation of β-catenin signaling. We tested the hypothesis that β-catenin is involved in mesenchymal lineage allocation to osteogenic cells using a β-catenin mutant with constitutive transcriptional activity (ΔN151). Although this stable β-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, ΔN151 and BMP-2 synergistically stimulated new bone formation after subperiosteal injection in mouse calvaria in vivo. Conversely, ΔN151 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, β-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.
AB - Mutations of critical components of the Wnt pathway profoundly affect skeletal development and maintenance, probably via modulation of β-catenin signaling. We tested the hypothesis that β-catenin is involved in mesenchymal lineage allocation to osteogenic cells using a β-catenin mutant with constitutive transcriptional activity (ΔN151). Although this stable β-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, ΔN151 and BMP-2 synergistically stimulated new bone formation after subperiosteal injection in mouse calvaria in vivo. Conversely, ΔN151 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, β-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.
KW - Adipogenesis
KW - Bone formation
KW - Cell-cell adhesion
KW - Mesenchymal differentiation
UR - http://www.scopus.com/inward/record.url?scp=17144373190&partnerID=8YFLogxK
U2 - 10.1002/jcb.20253
DO - 10.1002/jcb.20253
M3 - Article
C2 - 15526274
AN - SCOPUS:17144373190
SN - 0730-2312
VL - 94
SP - 403
EP - 418
JO - Journal of cellular biochemistry
JF - Journal of cellular biochemistry
IS - 2
ER -