Objective. Stromal cell-derived factor 1 (SDF-1; or, CXCL12) is a potent chemotactic and angiogenic factor that has been proposed to play a role in the recruitment of lymphocytes into rheumatoid arthritis (RA) synovium. We tested the hypothesis that synovial SDF-1 expression is regulated by cytokine and hypoxic stimulation, the latter being mediated by hypoxiainducible factor 1␣ (HIF-1␣). These factors regulate the expression of vascular endothelial growth factor (VEGF), itself an important angiogenic mediator.Methods. RA and osteoarthritic synovial fibroblasts and whole tissue explants were cultured under normoxic or hypoxic (1% O 2 ) conditions for up to 72 hours in the presence or absence of interleukin-1␤ (IL-1␤), tumor necrosis factor (TNF), or transforming growth factor ␤ (TGF␤). Expression of HIF-1␣, VEGF, and SDF-1 was detected in synovial tissue and cells by immunohistochemistry and Western blotting. VEGF and SDF-1 expression by cultured synovial fibroblasts was evaluated by reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay.Results. Immunohistochemistry revealed the presence of HIF-1␣, VEGF, and SDF-1 in RA synovium. Patchy expression of HIF-1␣ was detected primarily in the synovial lining and sublining areas; expression in synovial fibroblasts and in the lining cells of whole synovial tissue explants was markedly augmented by hypoxic culture conditions. Hypoxia enhanced the expression of VEGF and SDF-1 messenger RNA in synovial fibroblasts. The production of VEGF and SDF-1 protein by synovial fibroblasts was augmented by 50% and 132%, respectively, after 24 hours of hypoxia. VEGF production was potently induced by TGF␤, and to a lesser extent by IL-1␤ and TNF, and was further augmented by hypoxia. In contrast, none of the tested cytokines induced SDF-1 production.Conclusion. As with VEGF, SDF-1 expression is induced by hypoxia; however, cytokines induce VEGF but not SDF-1. Hypoxic conditions in RA synovium, which are likely to be transient and episodic, may contribute to the persistence of synovitis by inducing VEGF and SDF-1.

In a genetically predisposed population of NAN patients with RA and their relatives, anti-P. gingivalis antibodies were associated with ACPA. These findings suggest that immune responses to P. gingivalis may be involved in breaking immune tolerance to citrullinated antigens.

In a large, international cohort of patients with RA, 30% of CVD events were attributable to RA characteristics. This finding indicates that RA characteristics play an important role in efforts to reduce CVD risk among patients with RA.

265 AGE = advanced glycation endproducts; HIF-1α = hypoxia-inducible factor-1α; LDL = low-density-lipid proteins; MAP = mitogen-activated protein; MMR = mismatch repair; mtDNA = mitochondrial DNA; NF-κB = nuclear factor-κB; PHD = prolyl hydroxylase; PI-3K = phosphoinositide 3-kinase; RA = rheumatoid arthritis; RNS = reactive nitrogen species; ROS = reactive oxygen species; SOD = superoxide dismutase; TGF = transforming growth factor; TNF = tumor necrosis factor; VEGF = vascular endothelial growth factor; VHL = von Hippel-Landau tumor suppressor factor. Available online http://arthritis-research.com/content/6/6/265 Introduction Molecular oxygen is essential for the survival of all aerobic organisms. Aerobic energy generation is dependent on oxidative phosphorylation, a process by which the oxidoreduction energy of mitochondrial electron transport is converted to the high-energy phosphate bond of ATP. In this multi-step enzymatic process, oxygen serves as the final electron acceptor for cytochrome c oxidase, the terminal component of the mitochondrial enzymatic complex that catalyzes the four-electron reduction of O 2 to H 2 O. A byproduct of this process is the production of partly reduced oxygen metabolites that are highly reactive and that leak out of the mitochondria and react rapidly with other molecules. In turn, reactive nitrogen species, sulfur-centered radicals, and other reactive species are generated by interactions with these molecules. Reactive oxygen species (ROS) participate in several physiological functions, and form an integral part of the organism's defense against invading microbial agents.Because of their potentially damaging effects, several antioxidant mechanisms have evolved to protect cells and organisms from damage by excessive amounts of these highly reactive mediators. Oxidative stress is a term that is used to describe situations in which the organism's production of oxidants exceeds the capacity to neutralize them. The result can be damage to cell membranes, lipids, nucleic acids, proteins, and constituents of the extracellular matrix such as proteoglycans and collagens.Extended periods of hypoxia, or brief periods of complete anoxia, invariably lead to death. In contrast, cellular hypoxia occurs frequently, both physiologically and pathologically, and serves as a potent stimulus for changes in gene transcription, translation, and several post-translational protein modifications that serve to rapidly adapt cells and tissues to this stimulus. Oxygen levels vary considerably in different tissues -and even in different areas of a single tissue -and depend on a complex interaction of Review Oxidation in rheumatoid arthritis AbstractOxygen metabolism has an important role in the pathogenesis of rheumatoid arthritis. Reactive oxygen species (ROS) produced in the course of cellular oxidative phosphorylation, and by activated phagocytic cells during oxidative bursts, exceed the physiological buffering capacity and result in oxidative stress. The excessive production of ROS can damage protein...