Fibroblast activation protein is expressed by rheumatoid myofibroblast-like synoviocytes

Fibroblast activation protein (FAP), as described so far, is a type II cell surface serine protease expressed by fibroblastic cells in areas of active tissue remodelling such as tumour stroma or healing wounds. We investigated the expression of FAP by fibroblast-like synoviocytes (FLSs) and compared the synovial expression pattern in rheumatoid arthritis (RA) and osteoarthritis (OA) patients. Synovial tissue from diseased joints of 20 patients, 10 patients with refractory RA and 10 patients with end-stage OA, was collected during routine surgery. As a result, FLSs from intensively inflamed synovial tissues of refractory RA expressed FAP at high density. Moreover, FAP expression was co-localised with matrix metalloproteinases (MMP-1 and MMP-13) and CD44 splice variants v3 and v7/8 known to play a major role in the concert of extracellular matrix degradation. The pattern of signals appeared to constitute a characteristic feature of FLSs involved in rheumatoid arthritic joint-destructive processes. These FAP-expressing FLSs with a phenotype of smooth muscle actin-positive myofibroblasts were located in the lining layer of the synovium and differ distinctly from Thy-1-expressing and non-proliferating fibroblasts of the articular matrix. The intensity of FAP-specific staining in synovial tissue from patients with RA was found to be different when compared with end-stage OA. Because expression of FAP by RA FLSs has not been described before, the findings of this study highlight a novel element in cartilage and bone destruction of arthritic joints. Moreover, the specific expression pattern qualifies FAP as a therapeutic target for inhibiting the destructive potential of fibroblast-like synovial cells

Pseudoachondroplasia is caused through both intra- and extracellular pathogenic pathways

Pseudoachondroplasia is a dominantly inherited chondrodysplasia associated with mutations in cartilage oligomeric matrix protein (COMP). Investigations into the pathogenesis of pseudoachondroplasia are hampered by its rarity. We developed a cell culture model by expressing mutant COMP in bovine primary chondrocytes using a gutless adenoviral vector. We show that mutant COMP exerts its deleterious effects through both intra- and extracellular pathogenic pathways. Overexpression of mutant COMP led to a dose-dependent decrease in cellular viability. The secretion of mutant COMP was markedly delayed, presumably due to a prolonged association with chaperones in the endoplasmic reticulum (ER). The ECM lacked organized collagen fibers and showed amorphous aggregates formed by mutant COMP. Thus, pseudoachondroplasia appears to be an ER storage disease, most likely caused by improper folding of mutant COMP. The growth failure of affected patients may be explained by an increased cell death of growth-plate chondrocytes. Dominant interference of the mutant protein on collagen fiber assembly could contribute to the observed failure of the ECM of cartilage and tendons

Update on the profile of the EUSTAR cohort: an analysis of the EULAR Scleroderma Trials and Research group database

Objectives: Systemic sclerosis (SSc) is a rare disease requiring multicentre collaboration to reveal comprehensive details of disease-related causes for morbidity and mortality. Methods: The European League Against Rheumatism (EULAR) Scleroderma Trials and Research (EUSTAR) group initiated a database to prospectively gather key data of patients with SSc using a minimal essential dataset that was reorganised in 2008 introducing new items. Baseline visit data of patients who were registered between 2004 and 2011 were analysed using descriptive statistics. Results: In June 2011, 7655 patients (2838 with diffuse cutaneous (dc) and 4481 with limited cutaneous (lc) SSc who fulfilled the American College of Rheumatology diagnostic criteria had been registered in 174 centres, mainly European. The most prominent hallmarks of disease were Raynaud's phenomenon (96.3%), antinuclear antibodies (93.4%) and a typical capillaroscopic pattern (90.9%). Scleroderma was more common on fingers and hands than on any other part of the skin. Proton pump inhibitors (65.2%), calcium channel blockers (52.7%), and corticosteroids (45.3%) were most often prescribed. Among the immunosuppressant agents, cyclophosphamide was used more often in dcSSc than in lcSSc. Conclusions: The EUSTAR database provides an abundance of information on the true clinical face of SSc that will be helpful in improving the classification of SSc and its subsets and for developing more specific therapeutic recommendations