Background Syndecan-4 (sdc4) is a transmembrane heparan sulfate proteoglycan that in addition to functioning as an adhesion a molecule can bind cytokines and impact on inflammation. Modulation of inflammatory signals by sdc4 may occur either through mere binding of cytokines, in which case sdc4 acts as decoy receptor or through initiation of sdc-dependent signalling following sdc4 complex formation. While arthritic cartilage damage is decreased in sdc4-deficient mice most likely due to reduced sdc4 signaling, osteopontin- mediated liver damage has been shown to be increased in these mice due to the lack of scd4 decoy receptor function. Based on this dual and in part opposing effects of sdc4, the aim of this study was to investigate if the loss of sdc4 changes the natural course of murine experimental colitis. Methods Experimental Colitis was induced in sdc4-/- mice and in C57BL/6 WT mice by DSS. The course of colitis was monitored by weight loss as well as assessment of colon length and blinded histological scoring of colonic changes at the end of the experiment. In addition, sdc4-/- and C57BL/6 WT mice were orally gavaged with 5×108 colony-forming units (CFU) of Citrobacter rodentium. Fecal excretion of C rodentium and changes of body weight were monitored. At day 21 postinfection, inflammatory changes of the colon were evaluated histologically. Results Beginning from day 5 after start of DSS-administration, sdc4-/- mice lost dramatically more body weight compared to WT animals (day 8: 24.8%±1.9 vs 9.2%±3.1; p=0.008). In accordance with the increased loss of body weight, the colon length of sdc4-/- mice was significantly shortened (63.3 mm±2.4 vs 74.8±2.3; p=0.01) and the histological damage according to the Dieleman-Score was markedly aggravated (16AU±3.7 vs 3.4AU±0.2; p=0.016). At day 19 postinfection, the fecal excretion of C rodentium in sdc4-/- was prolonged compared to WT animals (2.5×105±6.8×103 vs 9.6×103±6.5×102; p=0.01). Histological damage of colonic mucosa, reflected by lengthening of crypts, was increased in Sdc4-/- mice (14.3AU±1.3 vs 10.2AU±0.9; p=0.03). Conclusions The data suggest that like in inflammatory liver damage, sdc4 exerts protective effects in intestinal inflammation. Future studies are needed to explore the underlying mechanisms and to determine if these effects are due to a decoy receptor function of sdc4 or whether sdc4 complex formation and signalling is involved.

Purpose Four-and-a-half LIM 2 (FHL2) is a mediator of protein interactions involved in cellular processes that are of relevance for the activation of mesenchymal cells.It interacts with integrins, focal adhesion-and mitogen-activated kinases, transcription factor AP-1 and is involved in TRAF6-dependent signalling.We analysed the function of FHL2 in chronic infl ammatory arthritis.Methods The expression of FHL2 in synovial tissues from patients with rheumatoid arthritis (RA) and osteoarthritis (OA) and in destructive arthritis of human tumour necrosis factor transgenic (hTNFtg) mice was analysed by immunohistochemistry. Fibroblast-like synoviocytes from patients with RA (RA-FLS), from hTNFtg mice and appropriate controls were isolated and FHL2 levels were determined by immunoblot after stimulation with cytokines.Knock down of FHL2 was performed by RNA interference and the expression of matrix metalloproteinases (MMPs) was determined by western blot analysis and ELISA.The invasiveness of FLS was analysed using our established matrix-associated transepithelial resistance invasion (MATRIN) assay.FHL2-mediated signalling pathways were also studied.hTNFtg mice were crossbred with FHL2-/-mice and clinical parameters of arthritis as well as histomorphometric parameters of joint destruction and MMP expression in wild-type, hTNFtg, FHL2-/-and FHL2+/-/ hTNFtg animals were analysed.Results Although there was a signifi cantly higher expression of FHL2 in RA than in OA, only transforming growth on July 20,

The activation of nuclear factor κB (NFκB) via RANK is essential in regulating osteoclastogenesis. Under inflammatory conditions this process is enhanced by cytokines such as tumour necrosis factor α (TNFα). P62/SQSTM1 directly modulates these pathways through complex formation with TRAF6, aPKCs and ubiquitin. However, the role of p62/SQSTM1 in regulating bone turnover under inflammatory conditions, and specifically the role of the signal transduction domains of p62/SQSTM1, is unclear. Mice were generated that carry a shortened but functional mutant of p62 with …

Integrins are the main receptors for cell-matrix interactions and integrin signalling is critical for a variety of cellular functions such as adhesion, cell spreading and inflammatory responses. α2β1 integrin functions as a major receptor for type I collagen on a number of different cells, including fibroblasts and inflammatory cells. Although α2-deficient mice appear normal apart from mild platelet dysfunction, it was shown that α2β1 integrin contributes to the induction of matrix metalloproteinases (MMPs) in tissue remodelling. Based on the hypothesis …

Rheumatoid arthritis (RA) is a chronic autoimmune disease of still unknown etiology that results in characteristic destructive changes of the joints. Research of the past years has demonstrated that synovial fibroblasts play a central role in the initiation and perpetuation of these destructive changes. Stimulation of the synovial fibroblasts through complex and interacting intracellular signaling pathways results in a stable activation that is maintain even without continuous stimulation by inflammatory cells and their mediators. The pathological attachment to articular cartilage, increased secretion of matrix degrading enzymes and alterations in programmed cell death are main characteristics of synovial fibroblasts from patients with RA and result in the progressive destruction of articular structures. The permanent activation of a number of intracellular signaling pathways constitutes the underlying responsible mechanism for the activation of synovial fibroblasts in RA. These signaling pathways do not only show a high degree of complexity, but are also interconnected in multiple ways. This article summarizes recent findings on the activation of intracellular signaling pathways in fibroblasts and points to potential targets for novel therapeutic strategies.

Background IL-21 is secreted by activated T cells and modulates immune cell functions with both proinflammatory and anti-inflammatory effects.IL-21 receptor (IL-21R), homologous to IL-2Rβ and IL-4Rα, associates with the gamma common chain upon ligand binding.It was recently described that IL-21R is overexpressed in the inflamed synovial membrane and on leucocytes of rheumatoid arthritis patients.Objective Previously we have shown that blockade of the IL-21 pathway with soluble IL-21R-Fc resulted in a reduction of clinical signs of arthritis in rodent models.To understand potential mechanisms of IL-21 regulation in arthritis, we analyzed serum immunoglobulin levels, and cytokine expression in the paws, serum, and collagen-restimulated splenocytes, in response to IL-21 pathway blockade.Methods Arthritis was induced in DBA/1 male mice with bovine type II collagen.Animals were treated with either soluble mIL-21R-Fc, which neutralizes murine IL-21 bioactivity, with TNFRII-Fc or with control IgG.Spleens from each group of treated mice were cultured in vitro with collagen and assayed for cytokine secretion.Cytokines and anticollagen-specific IgG levels were also measured in the serum by ELISA.Cytokine mRNA levels in the paws were evaluated by quantitative PCR analysis.Results Treatment of mice with IL-21R-Fc or TNFRII-Fc reduced clinical and histological signs of collagen-induced arthritis.IL-6 mRNA in paws and serum IL-6 levels were decreased after IL-21R-Fc treatment.IFNγ mRNA was increased in paws of IL-21R-Fctreated mice.Collagen-specific spleen cell responses from IL-21R-Fc-treated mice exhibited increased IFNγ and IL-2, and reduced IL-6 and IL-17 levels.Serum levels of total IgG 1 were also reduced in response to IL-21R-Fc treatment.Conclusion These data demonstrate a role for IL-21 in the modulation of collagen-specific T-cell responses and the pathology of arthritis, supporting a rationale for blockade of the IL-21 pathway in rheumatoid arthritis.