Fosl1 is a transcriptional target of c-Fos during osteoclast differentiation

Abstract

Osteoclasts are bone-resorbing cells derived from haematopoietic precursors of the monocyte-macrophage lineage. Mice lacking Fos (encoding c-Fos) develop osteopetrosis due to an early differentiation block in the osteoclast lineage1,2,3. c-Fos is a component of the dimeric transcription factor activator protein-1 (Ap-1), which is composed mainly of Fos (c-Fos, FosB, Fra-1 and Fra-2) and Jun proteins (c-Jun, JunB and JunD). Unlike Fra-1 (encoded by Fosl1), c-Fos contains transactivation domains required for oncogenesis and cellular transformation4,5,6. The mechanism by which c-Fos exerts its specific function in osteoclast differentiation is not understood. Here we show by retroviral-gene transfer that all four Fos proteins, but not the Jun proteins, rescue the differentiation block in vitro. Structure-function analysis demonstrated that the major carboxy-terminal transactivation domains of c-Fos and FosB are dispensable and that Fra-1 (which lacks transactivation domains4,7) has the highest rescue activity. Moreover, a transgene expressing Fra-1 rescues the osteopetrosis of c-Fos–mutant mice in vivo. The osteoclast differentiation factor Rankl (also known as TRANCE, ODF and OPGL; refs 811) induces transcription of Fosl1 in a c-Fos–dependent manner, thereby establishing a link between Rank signalling and the expression of Ap-1 proteins in osteoclast differentiation.

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Figure 1: Osteoclastogenic activity of Fos and Jun proteins in Fos−/− precursors.
Figure 2: Structure-function analysis of c-Fos and Fra-1.
Figure 3: Osteoclast formation induced by Fra-1 in Fos−/− mice.
Figure 4: Expression of Fosl1 in osteoclast-macrophage precursors.

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Acknowledgements

We thank M. Busslinger, H. Iba and R. Bravo for Ap-1 cDNAs; N. Schweifer for introduction to real-time PCR; W. Jochum for advice on histology; D. Mayr and M. Radolf for technical support; and M. Cotten, A.E. Grigoriadis and M. Bachler for critical reading of the manuscript. This work was partly supported by a grant from the Austrian Research Foundation (S7406-MOB) and the Austrian Industrial Research Promotion Fund.

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Correspondence to Erwin F. Wagner.

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Matsuo, K., Owens, J., Tonko, M. et al. Fosl1 is a transcriptional target of c-Fos during osteoclast differentiation . Nat Genet 24, 184–187 (2000) doi:10.1038/72855

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