This is an RSS newsfeed from BioMed Central It is intended to be used with an RSS reader. For more information about RSS newsfeeds from BioMed Central, visit http://www.biomedcentral.com/info/about/rss/ http://arthritis-research.com/ The latest articles from Arthritis Research & Therapy (ISSN 1478-6354) published by BioMed Central Epidemiological evidence indicates a significant association between vitamin D deficiency and an increased incidence of autoimmune diseases. The presence of vitamin D receptors in the cells of the immune system and the fact that several of these cells produce the vitamin D hormone suggested that it could have immunoregulatory properties and now potent immunomudulatory activities on dendritic cells, Th1 and Th17 cells, as well as on B cells are confirmed. Patients with undifferentiated connective tissue disease (UCTD) also show vitamin D deficiency and, interestingly, patients who progress into CTDs had the lower vitamin D levels than those who remained in UCTD stage. http://arthritis-research.com/content/10/6/123 Maurizio Cutolo Arthritis Research & Therapy 2008, 10:123 2008-12-02 doi:10.1186/ar2552 Arthritis Research & Therapy 1478-6354 10 123 2008-12-02 IntroductionWe recently described the ability of retinoid X receptor (RXR) ligand LG100268 (LG268) to inhibit IL-1beta-driven matrix metalloproteinase 1 (MMP-1) and MMP-13 gene expression in SW-1353 chondrosarcoma cells. Other investigators have demonstrated similar effects in chondrocytes treated with rosiglitazone, a ligand for peroxisome proliferator-activated receptor gamma (PPARgamma), for which RXR is an obligate dimerization partner. The goal of this study was to evaluate the inhibition of IL-1beta-induced expression of MMP-1 and MMP-13 by combinatorial treatment with RXR and PPARgamma ligands, and to investigate the molecular mechanisms of this inhibition. Methods: We used realtime RT-PCR to measure LG268- and rosiglitazone-mediated inhibition of MMP gene transcription in IL-1beta-treated SW-1353 chondrosarcoma cells. An in vitro collagen destruction assay was a functional readout of MMP collagenolytic activity. Luciferase reporter assays tested the function of a putative regulatory element in the promoters of MMP-1 and MMP-13, and chromatin immunoprecipitation (ChIP) assays detected PPARgamma and changes in histone acetylation at this site. Post-translational modification of RXR and PPARgamma by small ubiquitin-like modifier (SUMO) was assayed with immunoprecipitation and Western blot. Results: Rosiglitazone inhibited MMP-1 and MMP-13 expression in IL-1beta-treated SW-1353 cells at the mRNA and hnRNA levels, and blunted IL-1beta-induced collagen destruction in vitro. Combining LG268 and rosiglitazone had an additive inhibitory effect on MMP-1 and MMP-13 transcription and collagenolysis. IL-1beta inhibited luciferase expression in the MMP reporter assay, but rosiglitazone and LG268 had no effect. ChIP indicated that treatment with IL-1beta, but not LG268 and rosiglitazone, increased PPARgamma at the proximal promoters of both MMPs. Finally, rosiglitazone or LG268 induced "cross-SUMOylation" of both the target receptor and its binding partner, and IL-1beta-alone had no effect on SUMOylation of RXR and PPARgamma, but antagonized the ligand-induced SUMOylation of both receptors. Conclusions: The PPARgamma and RXR ligands rosiglitazone and LG268 may act through similar mechanisms, inhibiting MMP-1 and MMP-13 transcription. Combinatorial treatment activates each partner of the RXR:PPARgamma heterodimer and inhibits IL-1beta-induced expression of MMP-1 and MMP-13 more effectively than either compound alone. We conclude that the efficacy of combined treatment with lower doses of each drug may minimize potential side-effects of treatment with these compounds. http://arthritis-research.com/content/10/6/R139 Peter S Burrage, Adam C Schmucker, Yanqing Ren, Michael B Sporn and Constance E Brinckerhoff Arthritis Research & Therapy 2008, 10:R139 2008-12-01 doi:10.1186/ar2564 Arthritis Research & Therapy 1478-6354 10 R139 2008-12-01 Lupus nephritis is a major contributor to morbidity and mortality in systemic lupus erythematosus, but little is known about the pathogenic processes that underlie the progressive decay in renal function. A common finding in lupus nephritis is thickening of glomerular basement membranes associated with immune complex deposition. It has been speculated that alterations in the synthesis or degradation of membrane components might contribute to such changes, and thereby to initiation and progression of nephritis through facilitation of immune complex deposition. Matrix metalloproteinases (MMPs) are enzymes that are intimately involved in the turnover of major glomerular basement membrane constituents, including collagen IV and laminins. Alterations in the expression and activity of MMPs have been described in a number of renal diseases, suggesting their relevance to the pathogenesis of various glomerulopathies. The same is true for their natural inhibitors, the tissue inhibitor of metalloproteinase family. Recent data from our group have identified an increase in proteolytic activity within the glomerulus coinciding with the development of proteinuria in the mouse model of systemic lupus erythematosus. (NXB × NZW)F1 Here we review current understanding of MMP/tissue inhibitor of metalloproteinase function within the kidney, and discuss their possible involvement in the development and progression of lupus nephritis. http://arthritis-research.com/content/10/6/229 Anders Tveita, Ole Petter Rekvig and Svetlana N Zykova Arthritis Research & Therapy 2008, 10:229 2008-12-01 doi:10.1186/ar2532 Arthritis Research & Therapy 1478-6354 10 229 2008-12-01 IntroductionThe disease activity in patients with rheumatoid arthritis has improved during the past decade. The availability of new drugs and also a better assessment of the disease have been proposed to be responsible for this improvement. In the present work we estimate the effect of these factors on disease activity and function in patients with rheumatoid arthritis at the beginning of the new century. Methods: The Estudio de la Morbilidad y Expresión Clínica de la Artritis Reumatoide (EMECAR) cohort was assembled in 2000 from the random sampling of rheumatoid arthritis patients registered in 34 centers. The cohort was composed of 789 patients who underwent a baseline assessment plus four annual follow-up visits in which functional ability (Health Assessment Questionnaire score), the disease activity score obtained from 28-joint count with three parameters (DAS28-3) and radiological progression (Larsen score) were recorded. The effect of the calendar year on the DAS28-3, the Health Assessment Questionnaire score, and the Larsen score was obtained from adjusted models in which all treatments were included as dummy variables. Results: The effect of time as the β coefficient (95% confidence interval) for 2004, taking 2000 as a reference year, was -0.43 (-0.58 to -0.28) for the DAS28-3, 0.15 (0.07 to 0.22) for the Health Assessment Questionnaire score, and 4.4 (2.68 to 6.12) for the Larsen score. Treatment with new therapies, either leflunomide or TNF antagonists, increased in frequency from 1.1% (n = 8) in 2000 to 30.9% (n = 144) in 2004. Treatment with TNF antagonists (-0.28 (-0.5 to -0.05)) and with gold salts (-0.21 (-0.38 to -0.04)) was independently associated with a decrease in the DAS28-3 over time, whereas cyclosporin A treatment (0.45 (0.13 to 0.76)) was associated with an increase in disease activity. Conclusions: The mean disease activity of rheumatoid arthritis has improved from 2000 to 2004. An explanation is the introduction of new therapies, but not solely. Other factors related to the calendar year, plausibly a better management of available drugs, show a greater effect on improvement than the drugs used. http://arthritis-research.com/content/10/6/R138 Isidoro González-Alvaro, Miguel Angel Descalzo, Loreto Carmona and the EMECAR Study Group Arthritis Research & Therapy 2008, 10:R138 2008-11-26 doi:10.1186/ar2561 Arthritis Research & Therapy 1478-6354 10 R138 2008-11-26 IntroductionSjogren's syndrome is a systemic autoimmune disease in which an immunological attack primarily against the salivary and lacrimal glands results in loss of acinar cell tissue and function leading to stomatitis sicca and keratoconjunctivitis sicca. In recent years, two genetic regions, one on chromosome 1 (designated autoimmune exocrinopathy 2 or Aec2) and the second on chromosome 3 (designated autoimmune exocrinopathy 1 or Aec1) derived from non-obese diabetic mice, have been shown to be necessary and sufficient to replicate Sjogren's syndrome-like disease in non-susceptible C57BL/6 mice. Methods: Starting with the Sjogren's syndrome-susceptible C57BL/6-derived mouse, referred to as C57BL/6.NOD-Aec1Aec2, we generated a large set of recombinant inbred lines containing portions of autoimmune exocrinopathy 2 as a means of identifying more precisely the genetic elements of chromosome 1 responsible for disease development. Results: Disease profiling of these recombinant inbred lines has revealed that the Sjogren's syndrome-susceptibility genes of autoimmune exocrinopathy 2 lie within a region located at approximately 79 +/- 5 centimorgan distal to the centromere, as defined by microsatellite markers. This chromosomal region contains several sets of genes known to correlate with various immuno-pathological features of SjS, as well as disease susceptibility genes for both type 1 diabetes and systemic lupus erythematosus in mice. One gene in particular, tumor necrosis factor (ligand) superfamily, member 4 (or Ox40 ligand), encoding a product whose biological functions correlate with both physiological homeostasis and immune regulations, could be a potential candidate Sjogren's syndrome-susceptibility gene. Conclusions: These new recombinant inbred lines not only represent the first step in fine mapping a Sjogren's syndrome-susceptibility locus, but also in identifying potential candidate Sjogren's syndrome-susceptibility genes. Identification of possible candidate genes permits construction of models describing underlying molecular pathogenic mechanisms in this model of Sjogren's syndrome and establishes a basis for construction of specific gene knockout mice. http://arthritis-research.com/content/10/6/R137 Cuong Q Nguyen, Janet G Cornelius, Lauren Cooper, Jonathan Neff, Joann Tao, Byung Ha Lee and Ammon B Peck Arthritis Research & Therapy 2008, 10:R137 2008-11-25 doi:10.1186/ar2560 Arthritis Research & Therapy 1478-6354 10 R137 2008-11-25 Fibromyalgia: the labyrinth http://arthritis-research.com/content/10/6/409 Jean Eisinger Arthritis Research & Therapy 2008, 10:409 2008-11-25 doi:10.1186/ar2539 Arthritis Research & Therapy 1478-6354 10 409 2008-11-25 none http://arthritis-research.com/content/10/6/408 Denis Martinez and Cristiane Maria Cassol Arthritis Research & Therapy 2008, 10:408 2008-11-25 doi:10.1186/ar2538 Arthritis Research & Therapy 1478-6354 10 408 2008-11-25 The nucleotide-binding and oligomerization domain, leucine-rich repeat (also known as NOD-like receptors, both abbreviated to NLR) family of intracellular pathogen recognition receptors are increasingly being recognized to play a pivotal role in the pathogenesis of a number of rare monogenic diseases, as well as some more common polygenic conditions. Bacterial wall constituents and other cellular stressor molecules are recognized by a range of NLRs, which leads to activation of the innate immune response and upregulation of key proinflammatory pathways, such as IL-1β production and translocation of nuclear factor-κB to the nucleus. These signalling pathways are increasingly being targeted as potential sites for new therapies. This review discusses the role played by NLRs in a variety of inflammatory diseases and describes the remarkable success to date of these therapeutic agents in treating some of the disorders associated with aberrant NLR function. http://arthritis-research.com/content/10/6/228 Rebeccah J Mathews, Michael B Sprakes and Michael F McDermott Arthritis Research & Therapy 2008, 10:228 2008-11-25 doi:10.1186/ar2525 Arthritis Research & Therapy 1478-6354 10 228 2008-11-25 The paradigm for pathogenic autoimmunity is the generation of high-titre, affinity-matured autoantibodies to a restricted family of autoantigens, in the appropriate genetic context. Genetic determinants of autoimmunity are largely found within the major histocompatibility complex (MHC) and the "genotype to serotype to phenotype" concept is supported in a number of autoimmune diseases, where both genotype and serotype are well established. The serotype is autoantigen-driven, with evidence of epitope spreading as the disease evolves from asymptomatic to pathogenic autoimmunity. In rheumatoid arthritis and multiple sclerosis, where the autoantigens are poorly characterised, the use of an array in animal models may produce a hint of what happens in human disease. A more complete picture will be obtained from animals transgenic for human MCH, immunised with known human autoantigens. http://arthritis-research.com/content/10/6/122 Karin Lundberg and Patrick J Venables Arthritis Research & Therapy 2008, 10:122 2008-11-25 doi:10.1186/ar2544 Arthritis Research & Therapy 1478-6354 10 122 2008-11-25 IntroductionT-614 is a novel oral anti-rheumatic agent for the treatment of rheumatoid arthritis. Whether it has immunomodulatory or disease modifying properties and its mechanism of action are largely undetermined. Methods: Collagen-induced arthritis rats (CIA) were treated with T-614 (5 and 20mg/kg) daily. Methotrexate (MTX, 1mg/kg/3 days) and non-steroid anti-inflammatory agent -nimesulide (10mg/kg/day) were used as controls. A combination therapy group was treated with both T-614(10mg/kg/day) and methotrexate (1mg/kg/3 days). Hind-paw swelling and radiographic scores were evaluated. Serum cytokine levels were assessed by Bio-plex analysis. Quantitative polymerase chain reaction was used to evaluate expression of messenger RNA for interferon-gamma, interleukin-4 and interleukin-17. Serum interleukin-17 and anti- type II collagen antibodies (total IgG, IgG1, IgG2a, IgG2b and IgM) were measured by enzyme-linked immunosorbent assays, respectively. Results: Oral administration of T-614 could inhibit paw swelling and offered significant protection against arthritis-induced cartilage and bone erosion, which is compatible with methotrexate. Collagen-induced arthritis rats treated with T-614 presented decreases in both mRNA expression of interleukin-17 in peripheral blood mononuclear cells and lymph node cells, as well as circulating interleukin-17 level in a dose dependent manner. T-614 also reduced the serum levels of tumor necrosis factor-alpha (TNFalpha), interleukin-1beta (IL-1beta)and interleukin-6 (IL-6). Synergistic effect was observed in the combination of methotrexate and T-614. In addition, T-614(20mg/kg/day) could depress the anti- type II collagen antibodies production and differentially affected the levels of IgG2a immunoglobulin subclasses in vivo, while IgM level was decreased without any change in the IgG1 level. Collectively, T-614 prone to be a novel disease modifying antirheumatic drug (DMARD), as opposed to nimesulide, against experimental arthritis. Conclusions: Our data suggested that T-614 is an effective disease modifying agent to prevent the bone/cartilage destruction in collagen-induced arthritis rats significantly, as well as the inflammation. Combination with methotrexate enhances the therapeutic effect of T-614 prominently. http://arthritis-research.com/content/10/6/R136 Fang Du, Liangjing Lv, Qiong Fu, Min Dai, Wei Fan, Jialin Teng, Shunle Chen, Ping Ye, Nan Shen, Xinfang Huang, Jie Qian and Chunde Bao Arthritis Research & Therapy 2008, 10:R136 2008-11-19 doi:10.1186/ar2554 Arthritis Research & Therapy 1478-6354 10 R136 2008-11-19