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Arthritis Res. 2001; 3(Suppl A): L025.
Published online 2001 January 26. doi:  10.1186/ar169
PMCID: PMC3273243

Normal and pathological bone development controlled by the AP-1 transcription factor complex

c-Fos is a key regulator of bone development, since transgenic mice expressing exogenous Fos develop bone tumors, whereas mice lacking c-Fos are osteopetrotic due to a differentiation block in bone resorbing osteoclasts. We are interested to study how c-Fos and its related protein Fra-1, which is c-Fos inducible, control osteoblast proliferation and osteoclast differentiation (1). We recently found that Fra-1 is an essential gene for mouse development (2) and transgenic mice overexpressing Fra-1 develop the bone disease osteosclerosis, which is due to increased bone formation (3). To test whether Fra-1 can substitute for c-Fos, we generated knock-in mice that express Fra in place of c-Fos. Fra-1 rescues c-Fos dependent functions in bone development which appeared to be gene dosage dependent (4). However, Fra-1 failed to substitute for c-Fos in inducing expression of target genes in vitro. We are using these systems to identify novel Fos target genes by microarrays and with the help of bone-specific conditional alleles of c-Fos and Fra-1, we are studying the molecular mechanisms how Fos proteins govern bone cell development and differentiation.

Since Fos proteins need Jun proteins to activate transcription, we investigated the function of c-Jun in bone cells using the cre/loxP system. Chondrocyte-specific inactivation using col2A1-cre transgenic mice results in severe scoliosis caused by failure of intevertebral disk formation and abnormal vertebral arch development, suggesting that c-jun is a novel regulator of sklerotomal differentiation.

References

  • Matsuo K, Owens JM, Tonko M, Elliot C, Chambers TJ, Wagner EF. Osteoclast differentiation by the c-Fos target gene Fra-1, Nature Genetics. 2000;24:184–187. doi: 10.1038/72855. [PubMed] [Cross Ref]
  • Schreiber M, Wang ZQ, Jochum W, Fetka I, Elliott C, Wagner EF. Placental vascularization requires the AP-1 component Fra1. Development. 2000;127:4937–4948. [PubMed]
  • Jochum W, David JP, Elliot C, Wutz A, Plenk H, Matsuo K, Wagner EF. Increased bone formation in transgenic mice expressing the transcription factor Fra-1, Nature Medicine. 2000;6:980–984. doi: 10.1038/79676. [PubMed] [Cross Ref]
  • Fleischmann A, Hafezi F, Elliott C, Remé CE, Rüther U, Wagner EF. Fra-1 replaces c-Fos-dependent functions in mice. Genes & Development. 2000;14:2695–2700. doi: 10.1101/gad.187900. [PubMed] [Cross Ref]

Articles from Arthritis Research are provided here courtesy of BioMed Central