TY - JOUR
T1 - The pro-osteogenic action of β-catenin requires interaction with BMP signaling, but not Tcf/Lef transcriptional activity
AU - Salazar, Valerie S.
AU - Mbalaviele, Gabriel
AU - Civitelli, Roberto
PY - 2008/6/1
Y1 - 2008/6/1
N2 - The role of β-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 β-catenin to gain further insights on these mechanisms. Retroviral transduction of a full-length, constitutively active β-catenin mutant inhibited adipogenesis and stimulated osteoblast differentiation from multipotent embryonic fibroblasts (C3H10T1/2). However, N-terminal truncated β-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 β-catenin did not suppress adipogenesis, and even elicited spontaneous adipogenesis when expressed in cells cultured in osteogenic conditions. Thus, Tcf/Lef transcriptional activity of β-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 β-catenin mutant. C3H10T1/2 cells produce BMP-4, and inhibition of endogenous BMP signaling by Noggin curtailed osteogenic differentiation by constitutively active β-catenin. Therefore, BMP signaling must be active for full induction by β-catenin of osteogenic differentiation from multipotent precursors. These data suggest that cooperative interactions between β-catenin and BMP signaling systems drive osteoblast cell fate specification and differentiation.
AB - The role of β-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 β-catenin to gain further insights on these mechanisms. Retroviral transduction of a full-length, constitutively active β-catenin mutant inhibited adipogenesis and stimulated osteoblast differentiation from multipotent embryonic fibroblasts (C3H10T1/2). However, N-terminal truncated β-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 β-catenin did not suppress adipogenesis, and even elicited spontaneous adipogenesis when expressed in cells cultured in osteogenic conditions. Thus, Tcf/Lef transcriptional activity of β-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 β-catenin mutant. C3H10T1/2 cells produce BMP-4, and inhibition of endogenous BMP signaling by Noggin curtailed osteogenic differentiation by constitutively active β-catenin. Therefore, BMP signaling must be active for full induction by β-catenin of osteogenic differentiation from multipotent precursors. These data suggest that cooperative interactions between β-catenin and BMP signaling systems drive osteoblast cell fate specification and differentiation.
KW - Adipogenesis
KW - BMP
KW - Cell signaling
KW - Osteoblast differentiation
KW - β-catenin
UR - http://www.scopus.com/inward/record.url?scp=45149130750&partnerID=8YFLogxK
U2 - 10.1002/jcb.21679
DO - 10.1002/jcb.21679
M3 - Article
C2 - 18247340
AN - SCOPUS:45149130750
SN - 0730-2312
VL - 104
SP - 942
EP - 952
JO - Journal of cellular biochemistry
JF - Journal of cellular biochemistry
IS - 3
ER -