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

Nat Genet. 2000 Feb;24(2):184-7. doi: 10.1038/72855.

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 lineage. 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 transformation. 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 domains) 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins / metabolism
  • Cell Differentiation
  • Cells, Cultured
  • DNA-Binding Proteins / metabolism
  • Dimerization
  • Fos-Related Antigen-2
  • Genes, fos
  • Membrane Glycoproteins / metabolism
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Osteoclasts / cytology*
  • Osteoclasts / metabolism*
  • Proto-Oncogene Proteins c-fos / deficiency
  • Proto-Oncogene Proteins c-fos / genetics*
  • Proto-Oncogene Proteins c-fos / metabolism*
  • RANK Ligand
  • Receptor Activator of Nuclear Factor-kappa B
  • Reverse Transcriptase Polymerase Chain Reaction
  • Spleen / cytology
  • Transcription Factors / metabolism
  • Transcription, Genetic*

Substances

  • Carrier Proteins
  • DNA-Binding Proteins
  • Fos-Related Antigen-2
  • Fosl2 protein, mouse
  • Membrane Glycoproteins
  • Proto-Oncogene Proteins c-fos
  • RANK Ligand
  • Receptor Activator of Nuclear Factor-kappa B
  • Tnfrsf11a protein, mouse
  • Tnfsf11 protein, mouse
  • Transcription Factors
  • fos-related antigen 1