Activator protein 1 (Fos/Jun) functions in inflammatory bone and skin disease

Abstract

Activator protein 1 (AP-1) (Fos/Jun) is a transcriptional regulator composed of members of the Fos and Jun families of DNA binding proteins. The functions of AP-1 were initially studied in mouse development as well as in the whole organism through conventional transgenic approaches, but also by gene targeting using knockout strategies. The importance of AP-1 proteins in disease pathways including the inflammatory response became fully apparent through conditional mutagenesis in mice, in particular when employing gene inactivation in a tissue-specific and inducible fashion. Besides the well-documented roles of Fos and Jun proteins in oncogenesis, where these genes can function both as tumor promoters or tumor suppressors, AP-1 proteins are being recognized as regulators of bone and immune cells, a research area termed osteoimmunology. In the present article, we review recent data regarding the functions of AP-1 as a regulator of cytokine expression and an important modulator in inflammatory diseases such as rheumatoid arthritis, psoriasis and psoriatic arthritis. These new data provide a better molecular understanding of disease pathways and should pave the road for the discovery of new targets for therapeutic applications.

Figure 1

The activator protein 1 transcription factor. The dimeric activator protein 1 (AP-1) transcription factor is composed of Jun and Fos proteins. Jun proteins form homodimers or heterodimers with Fos proteins through their leucine-zipper domains. The different dimer combinations recognize different sequence elements in the promoters and enhancers of target genes. Only the classic TPA-responsive element with the consensus sequence TGACTCA is shown. The AP-1 dimers recognize the specific response elements via the basic domain that is adjacent to the leucine-zipper domain and represent an α-helical structure. Among the target genes of AP-1 are important regulators of cell proliferation, differentiation and apoptosis. Some AP-1 targets are implicated in pathogenic processes such as S100a8 and S100a9. Positively regulated (+), negatively regulated (-), or positively and negatively regulated (+/-) depending on the AP-1 dimer composition.

Figure 2

Heterogeneous JunB expression within lesional psoriatic skin. Immune reactivity of a monoclonal antibody against JunB within a psoriatic lesion. (a) Distinct anti JunB reactivity of a parakeratotic lesion. JunB expression is observed throughout all epidermal layers (left side, arrow), whereas it is reduced on the right side of the lesion (see arrow). (b) A different area of the same lesion. A virtual absence of nuclear reactivity is seen in basal keratinocytes, whereas strong nuclear activity is detected in the upper suprabasal epidermal layers ((a) and (b) arrows).

Figure 3

Inducible deletion of JunB and Jun and in the epidermis of adult mice. Mice carrying floxed alleles for the Jun and/or JunB locus were used to delete one or both genes in the epidermis by inducible Cre-recombinase activity. (a) Schematic representation of the floxed Jun and JunB loci before and after tamoxifen-induced activation of the Cre-ER-fusion protein, which is under the control of the keratin 5 promoter. (b) Eight-week-old mice were injected for five consecutive days with tamoxifen to activate Cre-mediated deletion of Jun and JunB. Two weeks after the last injection ((c), (e) and (g), control mice), the double-mutant mice ((d), (f) and (h)) showed a strong skin and arthritis phenotype reminiscent of psoriasis mainly affecting the (d) ears, (f) tail and (h) paws. H&E staining of (e) control mice and (f) mutant skin mice reflects the histological hallmarks of psoriasis with abnormally thickened epidermis, parakeratosis, hyperkeratosis and fingerlike epidermal projections into the dermis.

Figure 4

Distinct joint pathology in an inducible Jun mouse model of psoriasis. Microscopic images of a mouse toe from (a) a wildtype littermate control and (b)–(d) JunB/Jun double-mutant mice. Tartrate-resistant acid phosphatise-stained paraffin sections demonstrate (b) a proliferative periostitis affecting both the underlying bone as well as (c) the overlying nail base and dermis with numerous infiltrating neutrophilic granulocytes (antineutrophil NEU47 staining). In advanced stages, (b) an almost complete destruction of the distal phalanx and (d) bone erosions with osteoclasts invading the bone tissue (arrows) can be observed. In contrast, in transgenic mice expressing human TNFα, no destruction of the distal phalanx and no erosive arthritis of the distal interaphalangeal joints are found: (e) wildtype control and (f) tartrate-resistant acid phosphatase staining. (f) Pannus formation and osteoclast-mediated subchondral bone destruction, similar to human rheumatoid arthritis, is consistently observed (arrow). Magnification: (a), (b), (e) and (f), 50×; (c) and (d), 200×.