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    Lef1{Delta}N binds {beta}-catenin and increases osteoblast activity and trabecular bone mass

    J Biol Chem. 2011 Jan 26. [Epub ahead of print]

    Lymphoid enhancer binding factor (Lef) 1 is a Wnt-responsive transcription factor that associates with β-catenin. Lef1N lacks the first 113 amino acids of Lef1 and a well-characterized high affinity β-catenin binding domain present in the full-length protein. Both Lef1 isoforms bind DNA and regulate gene expression. To examine the role of Lef1N in osteoblasts, a Lef1N transgenic mouse line was constructed, which expressed Lef1N in committed osteoblasts. Lef1N transgenic mice had higher trabecular bone volume. However, histological analyses of tibial sections revealed no differences in osteoblast or osteoclast surface areas. In contrast, bone formation and mineral apposition rates, as well as osteocalcin levels were increased in Lef1N transgenic mice. These results demonstrate that Lif1N regulates osteoblasts.
    Authors: Hoeppner LH, Secreto FJ, Razidlo DF, et. al

    Lymphoid enhancer binding factor (Lef) 1 is a high mobility group protein best known as a Wnt-responsive transcription factor that associates with β-catenin. Lef1N lacks the first 113 amino acids of Lef1 and a well-characterized high affinity β-catenin binding domain present in the full-length protein. Both Lef1 isoforms bind DNA and regulate gene expression. We previously reported that Lef1 is expressed in proliferating osteoblasts and blocks osteocalcin expression, but Lef1N is only detectable in the later stages of osteoblast differentiation and promotes osteogenesis in vitro. Here we show that Lef1ΔN retains the ability to physically and functionally interact with β-catenin. Unlike what has been reported in T cells and colon cancer cell lines, Lef1ΔN activated gene transcription in the absence of exogenous β-catenin and cooperated with constitutively active β-catenin to further stimulate gene transcription in mesenchymal and osteoblastic cells. Residues at the amino-terminus of Lef1ΔN were required for β-catenin binding and the expression of osteoblast differentiation genes. To determine the role of Lef1N on bone formation in vivo, a Lef1N transgene was expressed in committed osteoblasts. The Lef1N transgenic mice had higher trabecular bone volume in the proximal tibiae and L5 vertebrae. Histological analyses of tibial sections revealed no differences in osteoblast or osteoclast surface areas. However, bone formation and mineral apposition rates, as well as osteocalcin levels were increased in Lef1N transgenic mice. Together our data indicated that Lef1ΔN binds β-catenin, stimulates gene expression, and promotes terminal osteoblast differentiation.

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