Fos/AP‐1 proteins in bone and the immune system

Abstract

The skeleton and the immune system share a variety of different cytokines and transcription factors, thereby mutually influencing each other. These interactions are not confined to the bone marrow cavity where bone cells and hematopoietic cells exist in proximity but also occur at locations that are target sites for inflammatory bone diseases. The newly established research area termed 'osteoimmunology' attempts to unravel these skeletal/immunological relationships. Studies towards a molecular understanding of inflammatory bone diseases from an immunological as well as a bone-centered perspective have been very successful and led to the identification of several signaling pathways that are causally involved in inflammatory bone loss. Induction of receptor activator of nuclear factor (NF)-kappaB ligand (RANKL) signals by activated T cells and subsequent activation of the key transcription factors Fos/activator protein-1 (AP-1), NF-kappaB, and NF for activation of T cells c1 (NFATc1) are in the center of the signaling networks leading to osteoclast-mediated bone loss. Conversely, nature has employed the interferon system to antagonize excessive osteoclast differentiation, although this counteracting activity appears to be overruled under pathological conditions. Here, we focus on Fos/AP-1 functions in osteoimmunology, because this osteoclastogenic transcription factor plays a central role in inflammatory bone loss by regulating genes like NFATc1 as well as the interferon system. We also attempt to put potential therapeutic strategies for inflammatory bone diseases in perspective.

Antiosteoporotic compounds from seeds of Cuscuta chinensis

“…Selective estrogen receptor modulators (SERMs), such as tamoxifen and raloxifene, can activate AP-1 site transcription (Paech et al, 1997) and AP-1 activation is important in osteoblastogenesis (Wagner and Eferl, 2005), so the effect of TSZ on AP-1 transcription activation was examined. HeLa cells were transiently co-transfected with a luciferase reporter gene construct containing six copies of a consensus AP-1 in front of a TATA-box, together with human ER␣ or ER␤ expression plasmids.…”

“…AP-1 is a transcription factor complex containing the proto-oncogenes jun, fos, and other family members, and this complex interacts with AP-1 binding sites in the promoters to activate genes involved in cell growth, differentiation, and development. It has been established that AP-1 proteins play important roles in bone formation and resorption (Wagner and Eferl, 2005), and raloxifene, a clinical used ER antagonist in the treatment of osteoporosis, can activate ER␤/AP-1 whereas estradiol has no such effect (Paech et al, 1997). Considering the important role of estrogen in maintaining the balance between osteoblasts and osteoclasts in bone homeostasis, hormone replacement therapy has been established regime for prevention of postmenopausal bone loss (Tuner et al, 1994).…”

CREB and AP‐1 activation regulates MKP‐1 induction by LPS or M‐CSF and their kinetics correlate with macrophage activation versus proliferation

“…2). AP-1 is not a single protein but a series of dimeric basic region-leucine zipper proteins that belong to the Jun (c-Jun, JunB, JunD), Fos (c-Fos, FosB, Fra-1 and Fra2), and ATF (ATF2, LRF1/ATF3, B-ATF, JDP1, JDP2) subfamilies, which recognize either 12-otetradecanoylphorbol-13-acetate response elements (5 0 -TGAG/CTCA-3 0 ) or cAMP response elements (CRE, 5 0 -TGACGTCA-3 0 ) [44]. To determine the DNA-binding proteins associated with the proximal promoter of MKP-1 in vivo, we performed chromatin immunoprecipitation assays with several Ab.…”

Stimulation of T cells up-regulates expression of Ifi202, an interferon-inducible lupus susceptibility gene, through activation of JNK/c-Jun pathway

“…Signals from both the TCR-CD3 complex and CD28 are required for JNK and AP-1 activation in T cells, and these signals may be integrated in a such a way as to mediate T cell activation and the induction of IL-2 transcription [19]. Moreover, AP-1 has also been reported to be important for the regulation of Th1 and Th2 cytokine genes [19,24].…”

“…The AP-1 transcription factor modulates the immune system through several different mechanisms [24]: (i) by activation of cytokine production in cooperation with transcription factors of the NFAT family in different cell types; (ii) by regulating differentiation of naïve Tcells into T-helper 1 (Th1) or Th2 cells; and (iii) by modulating the activity of the innate immune system. Most cytokine genes (including the IL-2 and IFN-γ) are regulated cooperatively by a transcription factor complex consisting of AP-1 and NFAT [24,25].…”