- Poster presentation
- Open Access
Bone cell differentiation and the role of Fos/AP-1 proteins
Arthritis Res Thervolume 5, Article number: 49 (2003)
Fos proteins such as Fos, FosB, Fra-1 and Fra-2 are key regulators of bone development. Transgenic mice expressing Fos develop osteoblastic bone tumors, whereas mice lacking Fos (Fos-/-) are osteopetrotic and lack bone-resorbing osteoclasts . The Fos-related protein Fra-1, itself a Fos target gene, is essential for mouse development, whereas transgenic mice overexpressing Fra-1 develop an osteoblastic bone disease, osteosclerosis . Interestingly, gene replacement of Fos by Fra-1 showed functional equivalence of these two proteins . To better understand how Fos and Fra-1 control osteoblast and osteoclast differentiation, we generated conditional alleles of Fos and Fra-1. The embryonic lethality of the Fra-1 knockout mice was rescued with a conditional allele of Fra-1 using MORE-cre mice. The mutant mice are viable but are osteopenic. Interestingly, conditional deletion of JunB with the same MORE-cre line also rescued the lethality, and the mutant mice developed severe osteoporosis. Finally, inactivation of Fra-2 gives rise to pups that also exhibit severe osteoporosis and die at birth, probably due to heart failure. The signal transduction pathways operating in osteoclastogenesis have been extensively studied and the events downstream of RANKL signalling are well described . Positive and negative regulatory loops are in place, which involve the activation NF-κB and JNK, eventually leading to the expression of Fos, an essential gene for osteoclast differentiation . Microarray analysis revealed that the expression of NFATc1 is abolished in Fos-/- precursors . However, introduction of an activated form of NFATc into Fos-/- precursor cells rescued the bone resorptive function and restored transcription of osteoclast marker genes. Recent experiments addressing the molecular events during osteoclast formation will be discussed.
Karsenty G, Wagner EF: Reaching a genetic and molecular understanding of skeletal development. Dev Cell. 2002, 2: 389-406. 10.1016/S1534-5807(02)00157-0.
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. Nat Med. 2000, 6: 980-984. 10.1038/79676.
Fleischmann A, Hafezi F, Elliott C, Remé CE, Rüther U, Wagner EF: Fra-1 replaces c-Fos-dependent functions in mice. Genes Dev. 2000, 14: 2695-2700. 10.1101/gad.187900.
Takayanagi H, Kim S, Koga T, Nishina H, Isshiki M, Yoshida H, Saiura A, Isobe M, Yokochi T, Inoue J-i, Wagner EF, Mak TW, Kodama T, Taniguchi T: Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev Cell. 2002, 3: 889-901. 10.1016/S1534-5807(02)00369-6.