The pro-osteogenic action of beta-catenin requires interaction with BMP signaling, but not Tcf/Lef transcriptional activity.
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.
Salazar
Valerie S
VS
Division of Bone and Mineral Diseases, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Mbalaviele
Gabriel
G
Civitelli
Roberto
R
D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002454:Cell Differentiation; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D009154:Mutation; D010012:Osteogenesis; D015398:Signal Transduction; D051822:T Cell Transcription Factor 1 / Q000378:metabolism*; D014158:Transcription, Genetic; D051176:beta Catenin / Q000378:metabolism*
D019485:Bone Morphogenetic Proteins; D051821:Lymphoid Enhancer-Binding Factor 1; D051822:T Cell Transcription Factor 1; D051176:beta Catenin