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J Cell Biochem. 2008 Jun 1;104(3):942-52. doi: 10.1002/jcb.21679.

The pro-osteogenic action of beta-catenin requires interaction with BMP signaling, but not Tcf/Lef transcriptional activity.

Author information

1
Division of Bone and Mineral Diseases, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

Abstract

The role of beta-catenin in skeletal development and osteogenic cell differentiation is well established, but the molecular mechanisms attending these effects remain largely unknown. We conducted a structure/function analysis of beta-catenin to gain further insights on these mechanisms. Retroviral transduction of a full-length, constitutively active beta-catenin mutant inhibited adipogenesis and stimulated osteoblast differentiation from multipotent embryonic fibroblasts (C3H10T1/2). However, N-terminal truncated beta-catenin mutants with weak Tcf/Lef activity retained their pro-osteogenic action, as did a constitutively stabilized mutant lacking the C-terminal Tcf/Lef transactivation domain. Importantly, this Tcf/Lef-defective beta-catenin did not suppress adipogenesis, and even elicited spontaneous adipogenesis when expressed in cells cultured in osteogenic conditions. Thus, Tcf/Lef transcriptional activity of beta-catenin is critical for inhibition of adipogenesis, while it is dispensable for its pro-osteogenic effect. BMP-2 greatly enhanced both osteogenesis and adipogenesis in the presence of the C-terminally truncated mutant, though it selectively enhanced only osteoblast differentiation in cells transduced with the full-length, Tcf/Lef active beta-catenin mutant. C3H10T1/2 cells produce BMP-4, and inhibition of endogenous BMP signaling by Noggin curtailed osteogenic differentiation by constitutively active beta-catenin. Therefore, BMP signaling must be active for full induction by beta-catenin of osteogenic differentiation from multipotent precursors. These data suggest that cooperative interactions between beta-catenin and BMP signaling systems drive osteoblast cell fate specification and differentiation.

PMID:
18247340
PMCID:
PMC3811910
DOI:
10.1002/jcb.21679
[Indexed for MEDLINE]
Free PMC Article

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