Psoriatic arthritis (PsA) is an inflammatory joint disease that is distinct from other chronic arthritides and which is frequently accompanied by psoriasis vulgaris (PsV) and seronegativity for rheumatoid factor. We conducted a genome-wide association study in 609 German individuals with PsA (cases) and 990 controls with replication in 6 European cohorts including a total of 5,488 individuals. We replicated PsA associations at HLA-C and IL12B and identified a new association at TRAF3IP2 (rs13190932, P = 8.56 × 10⁻¹⁷). TRAF3IP2 was also associated with PsV in a German cohort including 2,040 individuals (rs13190932, P = 1.95 × 10⁻³). Sequencing of the exons of TRAF3IP2 identified a coding variant (p.Asp10Asn, rs33980500) as the most significantly associated SNP (P = 1.13 × 10⁻²⁰, odds ratio = 1.95). Functional assays showed reduced binding of this TRAF3IP2 variant to TRAF6, suggesting altered modulation of immunoregulatory signals through altered TRAF interactions as a new and shared pathway for PsA and PsV

Variants in two genes of the IL-23 receptor (R) pathway have recently been shown to be associated with psoriasis vulgaris (PV). We were interested whether the risk conferred by these variants differs between psoriatic skin and joint disease. Four variants of the IL12B and IL23R genes were analyzed in 1,114 PV patients, 748 patients with psoriatic arthritis (PA) and 937 healthy controls before and after stratification for the major psoriasis risk allele at psoriasis susceptibility locus 1 (PSORS1). For both PA and PV, we detected the strongest association with two IL12B single-nucleotide polymorphisms and the corresponding haplotype as reflected by minimal P-values of 10(-7) and highest odds ratios of 1.50 (1.28-1.75) for rs6887695 in PA patients and 1.50 (1.27-1.76) for rs3212227 in the PV cohort, respectively. For IL23R, only rs11209026 showed an association. The results remained significant after correction for multiple testing. No difference was observed after stratification for the PSORS1 risk allele. While confirming recent reports on variants of the IL-23R pathway as susceptibility factors for PV, our study is the first to extend analysis of both genes to PA. However, our results indicate that these variants are not specific risk factors for arthritis, but relevant for susceptibility to psoriasis in general.

Objective. To investigate the significance and pathogenic potential of a highly conserved major type II collagen triple-helical epitope-specific antibody (U1; amino acids 494-504) in vivo and in vitro in patients with early rheumatoid arthritis (RA) and in experimental animal models of collagen-induced arthritis (CIA).Methods. U1-specific antibodies in sera from patients with early RA (with or without joint erosions) were analyzed. Disease progression in the CIA models in mice and rats with anti-U1 antibodies was compared. The pathogenicity of binding of monoclonal antibodies (mAb) UL1 and CIIF4 to the U1 epitope and the F4 epitope (aa 926-936), respectively, was compared in vivo and on chondrocyte cultures and preformed cartilage in vitro, using Fourier transform infrared microspectroscopy analysis. In addition, UL1-induced proteoglycan depletion in vivo in the presence and absence of the complement factor C5 was analyzed.Results. Increased levels of U1 antibodies were observed in patients with early RA, especially in association with joint erosions. A significant correlation of U1-specific antibodies with disease progression was found in rats and mice with CIA. UL1 mAb induced, whereas CIIF4 mAb inhibited, the progression of arthritis. Similarly, UL1, but not CIIF4, impaired matrix synthesis on chondrocyte cultures and adversely affected preformed cartilage. Furthermore, UL1 induced significant proteoglycan depletion in vivo 3 days after injection, even in the absence of C5.Conclusion. Antibody epitope specificity contributes significantly to the development of arthritis, and the early pathogenic events operate independent of inflammation both in vitro and in vivo.

Objective. The membrane-anchored metalloproteinase disintegrin ADAM15 is up-regulated in osteoarthritis and has been implicated in proteolysis and cell-matrix interactions. To address its role in cartilage metabolism, we performed an analysis of joint morphology in aging mice with a targeted inactivation of the ADAM15 gene (ADAM15 ؊/؊). In addition, a human chondrocyte cell line overexpressing ADAM15 was used to investigate the role of ADAM15 in an in vitro model of chondrocyte-matrix interactions.Methods. Knee joint sections from 3-, 6-, and 12-14-month-old ADAM15 ؊/؊ and wild-type (WT) 129/ SvJ mice were examined for synovial hyperplasia, cartilage degradation, and osteophyte formation. Stable transfection of the human T/C28a4 chondrocyte cell line with full-length human ADAM15 complementary DNA led to the establishment of ADAM15-overexpressing chondrocytes that were further analyzed for their capability to adhere to and to survive on cartilage matrix molecules (fibronectin and types II and VI collagen) under conditions of serum starvation. ADAM15 expression was investigated by reverse transcriptionpolymerase chain reaction and Western blotting. Results. Aging ADAM15؊/؊ mice exhibited accelerated development of osteoarthritic lesions compared with WT mice, and the difference was statistically significant at age 12 months. The osteoarthritic changes preferentially affected male ADAM15 ؊/؊ mice. ADAM15 overexpression in T/C28a4 cells led to the specific reinforcement of chondrocyte adhesion to cartilage types II and VI collagen, and this was associated with enhanced cell viability under conditions of serum starvation.Conclusion. The accelerated development of murine osteoarthritis in ADAM15 deficiency as well as the proadhesive and cell survival-promoting in vitro effect of ADAM15 overexpression suggest a homeostatic rather than a destructive role of ADAM15 in cartilage remodeling.ADAM15 belongs to a family of adamalysin (ADAM) metalloproteinase disintegrins (MDCs) that are membrane-anchored glycoproteins containing modular metalloproteinase, disintegrin, cysteine-rich, and epidermal growth factor-like domains, followed in most cases by a transmembrane region and a cytoplasmic tail (1). ADAMs have been implicated in fertilization, myogenesis, neurogenesis, and protein ectodomain shedding (for recent reviews, see refs. 1 and 2) and are also thought to play roles in cell-cell or cell-matrix adhesion through interactions with integrins (3,4) or syndecans (5,6).For ADAM15, a variety of potential functions have been postulated. Thus, cell-cell interaction studies using its recombinant extracellular domains provide experimental evidence for a role in integrin ligation (␣v␤3, ␣5␤1, ␣9␤1) (3,7,8). The localization to adherens junctions in endothelial cell cultures and an enhancement of cell-cell interactions in ADAM15-overexpressing fibroblasts (9) indicate a role in cell adhesion. In addition, ADAM15 contains a catalytic site consensus sequence for zinc-dependent metalloprotein-

Objective. Psoriatic arthritis (PsA) is a common inflammatory joint disease distinct from other chronic arthritides and frequently accompanied by psoriasis vulgaris. In a first genome-wide association study (GWAS), we were able to identify several genetic risk factors. However, even combined with previously identified factors, the genetic contribution to disease was not fully explained. Therefore, we undertook this study to investigate further 17 loci from our GWAS that did not reach genome-wide significance levels of association in the initial analysis.Methods. Twenty-one of 22 single-nucleotide polymorphisms were successfully genotyped in independent cohorts of 1,398 PsA patients and 6,389 controls and in a group of 964 German patients with psoriasis vulgaris.Results. Association with a RUNX3 variant, rs4649038, was replicated in independent patients and controls and resulted in a combined P value of 1.40 ؋