Lymphocyte enhancer‐binding factor 1 (Lef1) inhibits terminal differentiation of osteoblasts
- 2 November 2005
- journal article
- research article
- Published by Wiley in Journal of Cellular Biochemistry
- Vol. 97 (5), 969-983
- https://doi.org/10.1002/jcb.20702
Abstract
Lef1 is a transcriptional regulator of the Wnt/β-catenin signaling cascade. Wnts directly augment bone formation and osteoblast differentiation from mesenchymal stem cells by receptor-mediated pathways involving Lrp5 and Frizzled. We previously reported that Lef1 represses Runx2-dependent activation of the late osteoblast differentiation gene, osteocalcin. Lef1 is expressed in preosteoblasts but is undetectable in fully differentiated osteoblasts. To determine if downregulation of Lef1 is necessary for osteoblast maturation, we constitutively overexpressed Lef1 in MC3T3-E1 preosteoblasts. Lef1-overexpressing cells produced alkaline phosphatase (ALP) and osteocalcin later, and at lower levels than control cells. Moreover, the extracellular matrices of Lef1-overexpressing cell cultures never mineralized. To further examine the role of Lef1 in osteoblasts, we suppressed Lef1 expression in MC3T3-E1 cells by RNA interference. Transient expression of a Lef1 shRNA efficiently reduced murine Lef1 levels and transcriptional activity. Stable suppression of Lef1 in MC3T3 preosteoblasts did not affect proliferation or Runx2 levels; however, ALP production and matrix mineralization were accelerated by 3–4 days. Gene chip analyses identified 14 genes that are differentially regulated in Lef1-suppressed cells. These data outline a role for Lef1 in delaying osteoblast maturation and suggest that Lef1 controls the expression of multiple genes in osteoblasts. J. Cell. Biochem. 97: 969–983, 2006.Keywords
This publication has 76 references indexed in Scilit:
- Expression Profile of Osteoblast Lineage at Defined Stages of DifferentiationPublished by Elsevier BV ,2005
- Defining the impact of β-catenin/Tcf transactivation on epithelial stem cellsGenes & Development, 2005
- Canonical Wnt Signaling in Differentiated Osteoblasts Controls Osteoclast DifferentiationDevelopmental Cell, 2005
- Dickkopf-1 (DKK1) reveals that fibronectin is a major target of Wnt signaling in branching morphogenesis of the mouse embryonic lungDevelopmental Biology, 2005
- Histone Deacetylase 3 Interacts with Runx2 to Repress the Osteocalcin Promoter and Regulate Osteoblast DifferentiationJournal of Biological Chemistry, 2004
- Annexin VIII Is Differentially Expressed by Chondrocytes in the Mammalian Growth Plate During Endochondral Ossification and in Osteoarthritic CartilageJournal of Bone and Mineral Research, 2002
- Wnt-3A/β-Catenin Signaling Induces Transcription from the LEF-1 PromoterPublished by Elsevier BV ,2002
- Expression Pattern and Gene Characterization ofAsporinPublished by Elsevier BV ,2001
- Identification of a Wnt-Responsive Signal Transduction Pathway in Primary Endothelial CellsBiochemical and Biophysical Research Communications, 1999
- Isolation of the most immature population of murine fetal thymocytes that includes progenitors capable of generating T, B, and myeloid cells.The Journal of Experimental Medicine, 1996