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RoblastsT Pap1, A Baier2, I Meinecke2, PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/25447644 A Drynda1, R Gay3, W Neumann2, S Gay3 1Division of Experimental Rheumatology, Otto-von-Guericke-University, Magdeburg, Germany; 2Department of Orthopedic Surgery, Otto-vonGuericke-University, Magdeburg, Germany; 3Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Z ich, Switzerland Arthritis Res Ther 2003, 5(Suppl 3):43 (DOI 10.1186/ar844) The activation of synovial fibroblasts (SF) is a hallmark of rheumatoid arthritis, and the resistance of rheumatoid arthritis (RA)-SF against Fas-induced cell death is one of their characteristic features. However, the mechanisms that are responsible for the low susceptibility of RA-SF to programmed cell death and, specifically, the pathways that link altered apoptosis to their aggressive behavior are only incompletely understood. In our present studies, we have compared the susceptibility of synovial fibroblasts from RA and osteoarthritis (OA) patients to Fas-induced apoptosis, and have studied mechanisms that contribute to both the invasiveness of RA-SF and their resistance against apoptosis. As determined by different techniques (measurement of cytoplasmatic Tyrphostin AG 490 dose mononucleosomes and oligonucleosomes, FACS analysis), RA-SF were significantly less susceptible to Fas-induced cell death than OASF despite their abundant expression of Fas. Stimulation of RA-SF with tumor necrosis factor alpha (TNF-) did not induce apoptosis, but in a dose-dependent manner reduced Fas-mediated cell death. This was accompanied by the activation of NF-B and the upregulation of disease-relevant matrix metalloproteinases. Of interest, adenoviral gene transfer of TIMP-3 reduced the invasiveness of RA-SF in the SCIDmouse in vivo model of RA, and completely reversed the apoptosisinhibiting effect of TNF-, in part by reducing the activation of NF-B. The effects of TNF- on apoptosis were similar in OA-SF. However, RA-SF differed from OA-SF by their elevated expression of the small ubiquitin-like modifier sentrin-1/SUMO-1. Retroviral gene transfer of antisense and expression constructs of sentrin-1/SUMO-1 confirmed its involvement in the altered susceptibility of RA-SF to apoptosis. Analysis of the subcellular localization of sentrin-1/SUMO-1 and gene transfer of SUMO-1-specific proteases revealed that modifications of transcriptionally active nuclear proteins by sentrin-1/SUMO-1 contribute to the regulation of apoptosis and the production of matrixdegrading enzymes.45 Cell biology PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/26437915 of synovial inflammation and secondary osteoporosis in rheumatoid arthritisY Tanaka, Y Okada, S Nakayamada, K Nakano, K Fujii, K Saito First Department of Internal Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan Arthritis Res Ther 2003, 5(Suppl 3):45 (DOI 10.1186/ar846) Rheumatoid arthritis (RA) is a representative autoimmune disease characterized by lymphocyte accumulation and synovial proliferation, which are induced by inflammatory cytokines and adhesion molecules. Although periarticular as well as systemic osteoporosis and subsequent joint destruction are major complications of RA, the precise mechanisms remain unclear. Osteoblasts not only play a central role in bone formation by synthesizing bone matrix proteins, but they regulate osteoclast maturation by cognate interaction, resulting in bone resorption. RANKL expressed on osteoblasts provides essential signals to osteoclast progenitors for their maturation. We have proposed that the LFA-1/I.

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