Runx2 and Bone Morphogenic Protein 2 Regulate the Expression of an Alternative Lef1 Transcript During Osteoblast Maturation

Lymphoid Enhancer Binding Factor (Lef) 1 is a transcriptional effector of the Wnt/Lrp5/beta-catenin signaling cascade, which regulates osteoblast differentiation, bone density, and skeletal strength. In this study, we describe the expression and function of an alternative Lef1 isoform in osseous cells. Lef1 Delta N is a naturally occurring isoform driven by a promoter (p2) within the intron between exons 3 and 4 of Lef1. Lef1 Delta N is induced during late osteoblast differentiation. This is converse to the expression pattern of the full-length Lef1 protein, which as we previously showed, decreases during differentiation. Agonists of osteoblast maturation differentially affected Lef1 Delta N expression. BMP2 stimulated Lef1 Delta N expression, whereas Wnt3a blocked basal and BMP2-induced expression of Lef1 Delta N transcripts during osteoblast differentiation. We determined that the Lef1 Delta N p2 promoter is active in osteoblasts and Runx2 regulates its activity. Stable overexpression of Lef1 Delta N in differentiating osteoblasts induced the expression of osteoblast differentiation genes, osteocalcin and type I collagen. Taken together, our results suggest Lef1 AN is a crucial regulator of terminal differentiation in osseous cells. J. Cell. Physiol. 221: 480-489, 2009. (C) 2009 Wiley-Liss, Inc.