Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
The 6-O Extracellular Endosulfatases as Novel Regulators of Synovitis.
Hong1, Yoon Hoon, Otsuki1, Shuhei, Miyaki1, Shugeru, Caramez2, Beatriz, Taniguchi1, Noboru, Lotz1, Martin
As receptors or co-receptors, the heparan sulfate proteoglycans (HSPG) modulate the binding and signaling of various ligands to their specific receptors. The sulfation pattern of HSPG is critical in determining binding or release of ligands. The recently identified extracellular sulfatases (Sulf-1, -2) exert novel signaling mechanisms by regulating the binding of ligands to the 6-O sulfate on HSPG and thereby can modulate several signaling pathways that are involved in inflammation. The aim of this study was to analyze expression patterns of Sulf-1 and Sulf-2 and their role in experimental arthritis.
Sulf expression in normal and arthritic human and murine knee joints and in cultured human fibroblast-like synoviocytes (FLS) were analyzed by real-time PCR, immunohistochemistry and western blotting. The role of Sulf in arthritis pathogenesis was analyzed by using the antigen-induced arthritis (AIA) model in wild-type, Sulf1-/- and Sulf2-/- mice. IL-6, an important mediator in arthritis, was measured by ELISA in FLS subjected to Sulf silencing or over-expressing with siRNA or cDNA transfection.
Synovial tissues from humans with rheumatoid arthritis (RA) and mice with AIA showed increased expression of Sulf-1 and Sulf-2 than tissues from human osteoarthritis (OA) or surgically-induced OA in mice or normal knee. Cultured FLS from RA patients showed higher Sulf-1 and Sulf-2 expression as compared to FLS from OA patients. Treatment of FLS with IL-1b or TNFa increased Sulf-1 expression was more prominently than Sulf-2. The severity of AIA was significantly reduced in Sulf1-/- but not in Sulf2-/- mice and this was associated with reduced synovial leukocyte infiltration and pro-inflammatory cytokine expression such as IL-1b and IL-6. Sulf-1 over-expression in FLS enhanced and Sulf-1 silencing reduced IL-6 expression but did not alter the basal or IL-1b induced expression of Cox-2, MMP-3 or MMP-13.
Increased Sulf expression is observed in arthritic synovium and in IL-1b or TNFa activated FLS. Sulf-1 plays an important role in arthritis pathogenesis and this is at least in part mediated by the controlling IL-6 production. Thus, Sulf-1 represents a novel therapeutic target for inflammatory arthropathies.
To cite this abstract, please use the following information:
Hong, Yoon Hoon, Otsuki, Shuhei, Miyaki, Shugeru, Caramez, Beatriz, Taniguchi, Noboru, Lotz, Martin; The 6-O Extracellular Endosulfatases as Novel Regulators of Synovitis. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :369