TY - JOUR T1 - Signalling in osteoclasts and the role of Fos/AP1 proteins JF - Annals of the Rheumatic Diseases JO - Ann Rheum Dis SP - ii83 LP - ii85 DO - 10.1136/ard.62.suppl_2.ii83 VL - 62 IS - suppl 2 AU - E F Wagner AU - K Matsuo Y1 - 2003/11/01 UR - http://ard.bmj.com/content/62/suppl_2/ii83.abstract N2 - The analysis of genetically modified mice and cells has provided important new insights into the biological functions of the dimeric transcription factor complex AP1. The key components of AP1, the Fos and Jun proteins, have essential roles in bone development, because these proteins influence the activity of all bone cells, including chondrocytes, osteoblasts, and osteoclasts. New AP1 functions and their downstream effectors were recently discovered using conditional mutagenesis in the mouse as well as by genome-wide analysis of AP1 inducible genes, in particular in the osteoclast lineage.The signal transduction pathways operating in osteoclastogenesis have been extensively studied and how extracellular stimuli lead to the activation of key transcriptional programmes is beginning to be understood. The events downstream of macrophage colony-stimulating factor (M-CSF) and receptor activator of NF-κB ligand (RANKL) signalling are well described. Positive and negative regulatory loops are in place, which involve the activation of NF-κB and Jun N-terminal kinase (JNK), eventually leading to the expression of AP1/Fos, an essential regulator of osteoclast differentiation.AP1 consists of a large variety of dimers composed of members of the Fos proteins—Fos, FosB, Fra1, and Fra2; the three Jun proteins—Jun, JunB, and JunD; and ATF proteins (for review see Karsenty and Wagner1 and Jochum et al2). AP1 acts like a biosensor in cells and is often considered as a stress responsive transcription factor complex. Being at the receiving end of several signal transduction cascades, AP1 activity converts extracellular signals from, for example, growth factor receptors, through mitogen activated protein kinase (MAPK) into changes in gene expression via expression of AP1 responsive target genes. The activity of AP1 is regulated at different levels—transcriptional and post-transcriptional; it is also modulated by interactions with other transcriptional regulators. AP1 activity is implicated in a wide range of biological processes, including cell proliferation, differentiation, … ER -