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Molecular and Cellular Biology, April 2004, p. 2820-2830, Vol. 24, No. 7
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.7.2820-2830.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

FosB Induces Osteosclerosis and Decreases Adipogenesis by Two Independent Cell-Autonomous Mechanisms

Marie Kveiborg,^1, George Sabatakos,^1, Riccardo Chiusaroli,¹ Meilin Wu,¹ William M. Philbrick,² William C. Horne,¹ and Roland Baron^1*

Departments of Cell Biology and Orthopaedics,¹ Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06510²

Received 1 May 2003/ Returned for modification 27 June 2003/ Accepted 15 December 2003

Osteoblasts and adipocytes may develop from common bone marrow mesenchymal precursors. Transgenic mice overexpressing FosB, an AP-1 transcription factor, under the control of the neuron-specific enolase (NSE) promoter show both markedly increased bone formation and decreased adipogenesis. To determine whether the two phenotypes were linked, we targeted overexpression of FosB in mice to the osteoblast by using the osteocalcin (OG2) promoter. OG2-FosB mice demonstrated increased osteoblast numbers and an osteosclerotic phenotype but normal adipocyte differentiation. This result firmly establishes that the skeletal phenotype is cell autonomous to the osteoblast lineage and independent of adipocyte formation. It also strongly suggests that the decreased fat phenotype of NSE-FosB mice is independent of the changes in the osteoblast lineage. In vitro, overexpression of FosB in the preadipocytic 3T3-L1 cell line had little effect on adipocyte differentiation, whereas it prevented the induction of adipogenic transcription factors in the multipotential stromal cell line ST2. Also, FosB isoforms bound to and altered the DNA-binding capacity of C/EBPß. Thus, the inhibitory effect of FosB on adipocyte differentiation appears to occur at early stages of stem cell commitment, affecting C/EBPß functions. It is concluded that the changes in osteoblast and adipocyte differentiation in FosB transgenic mice result from independent cell-autonomous mechanisms.

Present address: Institute of Molecular Pathology, University of Copenhagen, 2100 Copenhagen, Denmark.

Present address: Procter & Gamble Pharmaceuticals, Mason, OH 45040.

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