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

Overview

Journal J Cell Physiol

Specialties Cell Biology
Physiology

Date 2009 Aug 4

PMID 19650108

Citations 23

Authors

Luke H Hoeppner

Frank Secreto

Eric D Jensen

Xiaodong Li

Rachel A Kahler

Jennifer J Westendorf

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

A Whole-Genome Scan Revealed Genomic Features and Selection Footprints of Mengshan Cattle.

Cheng H, Lyu Y, Liu Z, Li C, Qu K, Li S Genes (Basel). 2024; 15(9).

PMID: 39336704 PMC: 11431585. DOI: 10.3390/genes15091113.

Bone canonical Wnt signaling is downregulated in type 2 diabetes and associates with higher advanced glycation end-products (AGEs) content and reduced bone strength.

Leanza G, Cannata F, Faraj M, Pedone C, Viola V, Tramontana F Elife. 2024; 12.

PMID: 38598270 PMC: 11006415. DOI: 10.7554/eLife.90437.

Expression variations in ectodysplasin-A gene (eda) may contribute to morphological divergence of scales in haplochromine cichlids.

Wagner M, Bracun S, Duenser A, Sturmbauer C, Gessl W, Ahi E BMC Ecol Evol. 2022; 22(1):28.

PMID: 35272610 PMC: 8908630. DOI: 10.1186/s12862-022-01984-0.

Microcomputed Tomography and Histological Study of Bone Regeneration Using Tooth Biomaterial with BMP-2 in Rabbit Calvarial Defects.

Wadhwa P, Lee J, Zhao B, Cai H, Rim J, Jang H Scanning. 2021; 2021:6690221.

PMID: 34055133 PMC: 8131161. DOI: 10.1155/2021/6690221.

Genistein contributes to cell cycle progression and regulates oxidative stress in primary culture of osteoblasts along with osteoclasts attenuation.

Siddiqui S, Mahdi A, Arshad M BMC Complement Med Ther. 2020; 20(1):277.

PMID: 32917180 PMC: 7488498. DOI: 10.1186/s12906-020-03065-5.

References

Sun Y, Kolligs F, Hottiger M, Mosavin R, Fearon E, Nabel G . Regulation of beta -catenin transformation by the p300 transcriptional coactivator. Proc Natl Acad Sci U S A. 2000; 97(23):12613-8. PMC: 18812. DOI: 10.1073/pnas.220158597. View

Hovanes K, Li T, Munguia J, Truong T, Milovanovic T, Marsh J . Beta-catenin-sensitive isoforms of lymphoid enhancer factor-1 are selectively expressed in colon cancer. Nat Genet. 2001; 28(1):53-7. DOI: 10.1038/ng0501-53. View

Tutter A, Fryer C, Jones K . Chromatin-specific regulation of LEF-1-beta-catenin transcription activation and inhibition in vitro. Genes Dev. 2001; 15(24):3342-54. PMC: 312851. DOI: 10.1101/gad.946501. View

Kahler R, Galindo M, Lian J, Stein G, van Wijnen A, Westendorf J . Lymphocyte enhancer-binding factor 1 (Lef1) inhibits terminal differentiation of osteoblasts. J Cell Biochem. 2005; 97(5):969-83. DOI: 10.1002/jcb.20702. View

Giese K, Pagel J, Grosschedl R . Functional analysis of DNA bending and unwinding by the high mobility group domain of LEF-1. Proc Natl Acad Sci U S A. 1997; 94(24):12845-50. PMC: 24226. DOI: 10.1073/pnas.94.24.12845. View

Hovanes K, Li T, Waterman M . The human LEF-1 gene contains a promoter preferentially active in lymphocytes and encodes multiple isoforms derived from alternative splicing. Nucleic Acids Res. 2000; 28(9):1994-2003. PMC: 103301. DOI: 10.1093/nar/28.9.1994. View

Ishitani T, Matsumoto K, Chitnis A, Itoh M . Nrarp functions to modulate neural-crest-cell differentiation by regulating LEF1 protein stability. Nat Cell Biol. 2005; 7(11):1106-12. DOI: 10.1038/ncb1311. View

Katagiri T, Yamaguchi A, Komaki M, Abe E, Takahashi N, Ikeda T . Bone morphogenetic protein-2 converts the differentiation pathway of C2C12 myoblasts into the osteoblast lineage. J Cell Biol. 1994; 127(6 Pt 1):1755-66. PMC: 2120318. DOI: 10.1083/jcb.127.6.1755. View

Boland G, Perkins G, Hall D, Tuan R . Wnt 3a promotes proliferation and suppresses osteogenic differentiation of adult human mesenchymal stem cells. J Cell Biochem. 2004; 93(6):1210-30. DOI: 10.1002/jcb.20284. View

10.

de Jong D, van Zoelen E, Bauerschmidt S, Olijve W, Steegenga W . Microarray analysis of bone morphogenetic protein, transforming growth factor beta, and activin early response genes during osteoblastic cell differentiation. J Bone Miner Res. 2002; 17(12):2119-29. DOI: 10.1359/jbmr.2002.17.12.2119. View

11.

Merrill B, Gat U, Dasgupta R, Fuchs E . Tcf3 and Lef1 regulate lineage differentiation of multipotent stem cells in skin. Genes Dev. 2001; 15(13):1688-705. PMC: 312726. DOI: 10.1101/gad.891401. View

12.

Carlsson P, Waterman M, Jones K . The hLEF/TCF-1 alpha HMG protein contains a context-dependent transcriptional activation domain that induces the TCR alpha enhancer in T cells. Genes Dev. 1993; 7(12A):2418-30. DOI: 10.1101/gad.7.12a.2418. View

13.

Mariadason J, Bordonaro M, Aslam F, Shi L, Kuraguchi M, Velcich A . Down-regulation of beta-catenin TCF signaling is linked to colonic epithelial cell differentiation. Cancer Res. 2001; 61(8):3465-71. View

14.

Noh T, Gabet Y, Cogan J, Shi Y, Tank A, Sasaki T . Lef1 haploinsufficient mice display a low turnover and low bone mass phenotype in a gender- and age-specific manner. PLoS One. 2009; 4(5):e5438. PMC: 2673053. DOI: 10.1371/journal.pone.0005438. View

15.

Dasgupta R, Fuchs E . Multiple roles for activated LEF/TCF transcription complexes during hair follicle development and differentiation. Development. 1999; 126(20):4557-68. DOI: 10.1242/dev.126.20.4557. View

16.

Levanon D, Goldstein R, Bernstein Y, Tang H, Goldenberg D, Stifani S . Transcriptional repression by AML1 and LEF-1 is mediated by the TLE/Groucho corepressors. Proc Natl Acad Sci U S A. 1998; 95(20):11590-5. PMC: 21685. DOI: 10.1073/pnas.95.20.11590. View

17.

Kratochwil K, Dull M, Farinas I, Galceran J, Grosschedl R . Lef1 expression is activated by BMP-4 and regulates inductive tissue interactions in tooth and hair development. Genes Dev. 1996; 10(11):1382-94. DOI: 10.1101/gad.10.11.1382. View

18.

Hoppler S, Kavanagh C . Wnt signalling: variety at the core. J Cell Sci. 2007; 120(Pt 3):385-93. DOI: 10.1242/jcs.03363. View

19.

Skokowa J, Cario G, Uenalan M, Schambach A, Germeshausen M, Battmer K . LEF-1 is crucial for neutrophil granulocytopoiesis and its expression is severely reduced in congenital neutropenia. Nat Med. 2006; 12(10):1191-7. DOI: 10.1038/nm1474. View

20.

Travis A, Amsterdam A, Belanger C, Grosschedl R . LEF-1, a gene encoding a lymphoid-specific protein with an HMG domain, regulates T-cell receptor alpha enhancer function [corrected]. Genes Dev. 1991; 5(5):880-94. DOI: 10.1101/gad.5.5.880. View