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Overexpression of ΔFosB transcription factor(s) increases bone formation and inhibits adipogenesis

Abstract

Members of the AP-1 family of transcription factors participate in the regulation of bone cell proliferation and differentiation. We report here a potent AP-1-related regulator of osteoblast function: ΔFosB, a naturally occurring truncated form of FosB that arises from alternative splicing of the fosB transcript and is expressed in osteoblasts. Overexpression of ΔFosB in transgenic mice leads to increased bone formation throughout the skeleton and a continuous post-developmental increase in bone mass, leading to osteosclerosis. In contrast, ΔFosB inhibits adipogenesis both in vivo and in vitro, and downregulates the expression of early markers of adipocyte differentiation. Because osteoblasts and adipocytes are thought to share a common precursor, it is concluded that ΔFosB transcriptionally regulates osteoblastogenesis, possibly at the expense of adipogenesis.

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Figure 1: Increased bone density and tissue-specific expression of ΔFosB isoforms in the NSE-ΔFosB mice.
Figure 2: Progressive osteosclerosis in mice overexpressing ΔFosB.
Figure 3: Cell-autonomous increased osteoblastogenesis in primary calvarial cultures of ΔFosB mice.
Figure 4: Decreased adipogenesis in primary calvarial and bone marrow stromal cell cultures of ΔFosB mice.
Figure 5: Molecular in vitro analysis of the role of ΔFosB isoforms during osteoblast differentiation.

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Acknowledgements

The authors thank Nancy Troiano, Jennifer Juel, Cathy Steffen and Emilia DiDomenico for expert technical assistance. We also thank A. Houghton and W. C. Horne for many helpful discussions and critical reading of the manuscript; G. Karsenty and P. Ducy for providing cDNA probes and the CBFA1 antisera; S. Roman-Roman for supplying rhBMP-2. This work was supported in part by Hoechst Marion Roussel.

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Sabatakos, G., Sims, N., Chen, J. et al. Overexpression of ΔFosB transcription factor(s) increases bone formation and inhibits adipogenesis. Nat Med 6, 985–990 (2000). https://doi.org/10.1038/79683

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