title: Differential effects of the antioxidant n-acetylcysteine on the production of catabolic mediators in IL-1beta-stimulated human osteoarthritic synoviocytes and chondrocytes.
abstract: Oxidative stress may play a relevant role in synovial inflammation and subsequently on cartilage damage during osteoarthritis development. We have assessed how the antioxidant N-acetylcysteine (NAC) affects the expression of different proinflammatory and structural mediators in human stimulated osteoarthritic synoviocytes and chondrocytes. Synovial membrane and articular cartilage were obtained from the osteoarthritis knees of patients who underwent joint replacement surgery. In cells stimulated with IL-1beta (10U/mL), the effects of NAC (2mmol/L) were tested at the mean peak plasma level following oral administration of therapeutic doses and its influence on prostaglandin E2 (PGE(2)) production, cyclooxigenase-2 (COX-2) expression, nitric oxide (NO) synthesis, nuclear factor kappa B (NF-kappaB) activation, and metalloproteinase-1 (MMP-1) and metalloproteinase-13 (MMP-13) expression were evaluated. While NAC significantly diminished PGE(2) release and the expression of both COX-2 and MMP-13 protein in IL-1beta-stimulated synoviocytes, it failed to modify their production in stimulated chondrocytes. Likewise, NAC only inhibited IL-1beta-stimulated NF-kappaB activation in synoviocytes. No inhibition of IL-1beta-induced NO synthesis by chondrocytes was observed following NAC incubation, while synoviocytes did not release detectable levels of NO. NAC did not induce changes in MMP-1 protein expression in either IL-1beta-stimulated synoviocytes or chondrocytes. Thus, NAC decreases the synthesis of several catabolic mediators by osteoarthritic synoviocytes, whereas, it failed to produce the same effects in osteoarthritic chondrocytes. Our results suggest that NAC inhibits some oxygen-dependent mechanisms in synoviocytes but not in chondrocytes during osteoarthritis. Therefore, NAC might have a symptomatic effect on the synovium rather than a structural effect on the cartilage in osteoarthritis.
authors.affiliation: Joint and Bone Research Unit, Rheumatology Service, Fundación Jiménez Díaz, Universidad Autónoma, Madrid, Spain.
authors.forename: Jorge A
authors.initials: JA
authors.lastname: Roman-Blas
authors.forename: María A
authors.initials: MA
authors.lastname: Contreras-Blasco
authors.forename: Raquel
authors.initials: R
authors.lastname: Largo
authors.forename: María A
authors.initials: MA
authors.lastname: Alvarez-Soria
authors.forename: Santos
authors.initials: S
authors.lastname: Castañeda
authors.forename: Gabriel
authors.initials: G
authors.lastname: Herrero-Beaumont
mesh_terms: D000111:Acetylcysteine / Q000378:metabolism / Q000494:pharmacology*; D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology*; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects* / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D018836:Inflammation Mediators; D053583:Interleukin-1beta / Q000378:metabolism / Q000494:pharmacology*; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide; D009573:Nitrites / Q000378:metabolism; D020370:Osteoarthritis, Knee / Q000378:metabolism*; D013347:Subcellular Fractions / Q000201:enzymology / Q000378:metabolism; D013583:Synovial Membrane / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000975:Antioxidants; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D016328:NF-kappa B; D009573:Nitrites; D009569:Nitric Oxide; D051546:Cyclooxygenase 2; D053509:Matrix Metalloproteinase 13; D020781:Matrix Metalloproteinase 1; D015232:Dinoprostone; D000111:Acetylcysteine