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Volume 3 Supplement 2

21st European Workshop for Rheumatology Research

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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.


  1. 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. 10.1038/72855.

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  2. 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.

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  3. 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. 10.1038/79676.

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  4. 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. 10.1101/gad.187900.

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Wagner, E. Normal and pathological bone development controlled by the AP-1 transcription factor complex. Arthritis Res Ther 3 (Suppl 2), L025 (2001).

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