Hoeppner Luke H, Secreto Frank, Jensen Eric D, Li Xiaodong, Kahler Rachel A, Westendorf Jennifer J
Graduate Program in Microbiology, Immunology and Cancer Biology, University of Minnesota, Minneapolis, MN, USA.
J Cell Physiol. 2009 Nov;221(2):480-9. doi: 10.1002/jcp.21879.
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. Lef1DeltaN is a naturally occurring isoform driven by a promoter (p2) within the intron between exons 3 and 4 of Lef1. Lef1DeltaN 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 Lef1DeltaN expression. BMP2 stimulated Lef1DeltaN expression, whereas Wnt3a blocked basal and BMP2-induced expression of Lef1DeltaN transcripts during osteoblast differentiation. We determined that the Lef1DeltaN p2 promoter is active in osteoblasts and Runx2 regulates its activity. Stable overexpression of Lef1DeltaN in differentiating osteoblasts induced the expression of osteoblast differentiation genes, osteocalcin and type 1 collagen. Taken together, our results suggest Lef1DeltaN is a crucial regulator of terminal differentiation in osseous cells.
淋巴增强因子结合因子（Lef）1是Wnt/Lrp5/β-连环蛋白信号级联的转录效应因子，该信号级联调节成骨细胞分化、骨密度和骨骼强度。在本研究中，我们描述了一种替代性Lef1异构体在骨细胞中的表达和功能。Lef1DeltaN是一种天然存在的异构体，由Lef1第3和第4外显子之间内含子中的启动子（p2）驱动。Lef1DeltaN在成骨细胞分化后期被诱导。这与全长Lef1蛋白的表达模式相反，正如我们之前所表明的，全长Lef1蛋白在分化过程中减少。成骨细胞成熟激动剂对Lef1DeltaN表达有不同影响。BMP2刺激Lef1DeltaN表达，而Wnt3a在成骨细胞分化过程中阻断Lef1DeltaN转录本的基础表达和BMP2诱导的表达。我们确定Lef1DeltaN p2启动子在成骨细胞中具有活性，并且Runx2调节其活性。在分化的成骨细胞中稳定过表达Lef1DeltaN可诱导成骨细胞分化基因骨钙素和I型胶原蛋白的表达。综上所述，我们的结果表明Lef1DeltaN是骨细胞终末分化的关键调节因子。
