Lymphocyte enhancer-binding factor 1 (Lef1) inhibits terminal differentiation of osteoblasts

Rachel A. Kahler, Mario Galindo, Jane Lian, Gary S. Stein, Andre J van Wijnen, Jennifer J Westendorf

Research output: Contribution to journalArticle

54 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)969-983
Number of pages15
JournalJournal of Cellular Biochemistry
Volume97
Issue number5
DOIs
StatePublished - Apr 1 2006
Externally publishedYes

Fingerprint

Lymphocytes
Osteoblasts
Genes
Osteocalcin
Alkaline Phosphatase
Catenins
Level control
RNA Interference
Oligonucleotide Array Sequence Analysis
Stem cells
Mesenchymal Stromal Cells
Cell culture
Osteogenesis
Small Interfering RNA
Extracellular Matrix

Keywords

  • Collagens
  • Matrix mineralization
  • Runx2
  • Wnt

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology

Cite this

Lymphocyte enhancer-binding factor 1 (Lef1) inhibits terminal differentiation of osteoblasts. / Kahler, Rachel A.; Galindo, Mario; Lian, Jane; Stein, Gary S.; van Wijnen, Andre J; Westendorf, Jennifer J.

In: Journal of Cellular Biochemistry, Vol. 97, No. 5, 01.04.2006, p. 969-983.

Research output: Contribution to journalArticle

Kahler, Rachel A. ; Galindo, Mario ; Lian, Jane ; Stein, Gary S. ; van Wijnen, Andre J ; Westendorf, Jennifer J. / Lymphocyte enhancer-binding factor 1 (Lef1) inhibits terminal differentiation of osteoblasts. In: Journal of Cellular Biochemistry. 2006 ; Vol. 97, No. 5. pp. 969-983.
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