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 8–11) 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.
Subscribe to Journal
Get full journal access for 1 year
only $18.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Wang, Z.Q. et al. Bone and haematopoietic defects in mice lacking c-fos. Nature 360, 741–745 ( 1992).
Johnson, R.S., Spiegelman, B.M. & Papaioannou, V. Pleiotropic effects of a null mutation in the c- fos proto-oncogene. Cell 71, 577– 586 (1992).
Grigoriadis, A.E. et al. c-Fos: a key regulator of osteoclast-macrophage lineage determination and bone remodeling. Science 266, 443– 448 (1994).
Wisdon, R. & Verma, I.M. Transformation by Fos proteins requires a C-terminal transactivation domain. Mol. Cell. Biol. 13, 7429–7438 (1993).
Jooss, K.U., Funk, M. & Müller, R. An autonomous N-terminal transactivation domain in Fos protein plays a crucial role in transformation. EMBO J. 13, 1467–1475 (1994).
Funk, M., Poensgen, B., Graulich, W., Jerome, V. & Müller, R. A novel, transformation-relevant activation domain in Fos proteins. Mol. Cell. Biol. 17, 537–544 (1997).
Bergers, G., Graninger, P., Braselmann, S., Wrighton, C. & Busslinger, M. Transcriptional activation of the fra-1 gene by AP-1 is mediated by regulatory sequences in the first intron . Mol. Cell. Biol. 15, 3748– 3758 (1995).
Wong, B.R. et al. TRANCE (tumor necrosis factor [TNF]-related activation-induced cytokine), a new TNF family member predominantly expressed in T cells, is a dendritic cell-specific survival factor. J. Exp. Med. 186, 2075–2080 (1997).
Anderson, D.M. et al. A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature 390, 175–179 (1997).
Yasuda, H. et al. Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc. Natl Acad. Sci. USA 95, 3597–3602 ( 1998).
Lacey, D.L. et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93, 165–176 (1998).
Kustikova, O. et al. Fra-1 induces morphological transformation and increases in vitro invasiveness and motility of epithelioid adenocarcinoma cells. Mol. Cell. Biol. 18, 7095–7105 (1998).
Grigoriadis, A.E., Schellander, K., Wang, Z.Q. & Wagner, E.F. Osteoblasts are target cells for transformation in c-fos transgenic mice. J. Cell Biol. 122, 685–701 (1993).
Sutherland, J.A., Cook, A., Bannister, A.J. & Kouzarides, T. Conserved motifs in Fos and Jun define a new class of activation domain. Genes Dev. 6, 1810–1819 (1992).
Metz, R. et al. c-Fos-induced activation of a TATA-box-containing promoter involves direct contact with TATA-box-binding protein. Mol. Cell. Biol. 14, 6021–6029 ( 1994).
Metz, R., Kouzarides, T. & Bravo, R. A C-terminal domain in FosB, absent in FosB/SF and Fra-1, which is able to interact with the TATA binding protein, is required for altered cell growth. EMBO J. 13, 3832– 3842 (1994).
Wisdom, R., Yen, J., Rashid, D. & Verma, I.M. Transformation by FosB requires a trans-activation domain missing in FosB2 that can be substituted by heterologous activation domains. Genes Dev. 6, 667–675 (1992).
Oliviero, S., Robinson, G.S., Struhl, K. & Spiegelman, B.M. Yeast GCN4 as a probe for oncogenesis by AP-1 transcription factors: transcriptional activation through AP-1 sites is not sufficient for cellular transformation . Genes Dev. 6, 1799–1809 (1992).
Wrighton, C. & Busslinger, M. Direct transcriptional stimulation of the ornithine decarboxylase gene by Fos in PC12 cells but not in fibroblasts . Mol. Cell. Biol. 13, 4657– 4669 (1993).
Owens, J.M., Matsuo, K., Nicholson, G.C., Wagner, E.F. & Chambers, T.J. Fra-1 potentiates osteoclastic differentiation in osteoclast-macrophage precursor cell lines. J. Cell. Physiol. 179, 170–178 (1999).
Hsu, H. et al. Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand. Proc. Natl Acad. Sci. USA 96, 3540– 3545 (1999).
Russell, R.G.G. & Rogers, M.J. Bisphosphonates: from the laboratory to the clinic and back again. Bone 25, 97–106 (1999).
Schreiber, M. et al. Structure and chromosomal assignment of the mouse fra-1 gene, and its exclusion as a candidate gene for oc (osteosclerosis). Oncogene 15, 1171–1178 ( 1997).
Kong, Y.Y. et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 397 , 315–323 (1999).
Dougall, W.C. et al. RANK is essential for osteoclast and lymph node development . Genes Dev. 13, 2412–2424 (1999).
Morgenstern, J.P. & Land, H. Advanced mammalian gene transfer: high titre retroviral vectors with multiple drug selection markers and a complementary helper-free packaging cell line. Nucleic Acids Res. 18, 3587–3596 (1990).
Chambers, T.J., Owens, J.M., Hattersley, G., Jat, P.S. & Noble, M.D. Generation of osteoclast-inductive and osteoclastogenic cell lines from the H-2KbtsA58 transgenic mouse. Proc. Natl Acad. Sci. USA 90, 5578– 5582 (1993).
Livak, K.J., Flood, S.J., Marmaro, J., Giusti, W. & Deetz, K. Oligonucleotides with fluorescent dyes at opposite ends provide a quenched probe system useful for detecting PCR product and nucleic acid hybridization. PCR Methods Appl. 4, 357–362 (1995).
Brown, H.J., Sutherland, J.A., Cook, A., Bannister, A.J. & Kouzarides, T. An inhibitor domain in c-Fos regulates activation domains containing the HOB1 motif. EMBO J. 14, 124–131 ( 1995).
Gius, D. et al. Transcriptional activation and repression by Fos are independent functions: the C terminus represses immediate-early gene expression via CArG elements. Mol. Cell. Biol. 10, 4243– 4255 (1990).
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.
About this article
Cite this article
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
Hippuric acid and 3‐(3‐hydroxyphenyl) propionic acid inhibit murine osteoclastogenesis through RANKL‐RANK independent pathway
Journal of Cellular Physiology (2020)
Gene Expression Profiles of Peripheral Blood Monocytes in Osteoarthritis and Analysis of Differentially Expressed Genes
BioMed Research International (2019)
Biochemical and Biophysical Research Communications (2019)
Accelerated evolution and diversifying selection drove the adaptation of cetacean bone microstructure
BMC Evolutionary Biology (2019)
Artemisinin inhibits breast cancer‐induced osteolysis by inhibiting osteoclast formation and breast cancer cell proliferation
Journal of Cellular Physiology (2019)