Exacerbation of antigen-induced arthritis in inducible nitric oxide synthase-deficient mice

Abstract

Objective Inhibition of nitric oxide (NO) produced by inducible NO synthase (iNOS) is suggested to be beneficial in experimental arthritis. Although NO is important for the integrity of the microcirculation, the effects of inhibition of iNOS on the synovial microcirculation are not currently known. This study investigated the synovial microcirculation and leukocyte–endothelial cell interactions in iNOS‐deficient mice with antigen‐induced arthritis (AIA) and compared these findings with disease severity. Methods Fourteen homozygous iNOS−/− and 14 iNOS+/+ mice were used. The severity of AIA was assessed by measuring knee joint swelling and by histologic scoring. The number of rolling and adherent leukocytes was quantitatively analyzed in synovial microvessels using intravital microscopy of intraarticular synovial tissue. Nitrite/nitrate concentrations were measured, and the expression of iNOS, E‐ and P‐selectin, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1 (VCAM‐1) was assessed by immunohistochemistry. Results In iNOS+/+ animals with AIA, the plasma concentration of nitrite/nitrate was increased 3‐fold and iNOS expression was detected in cells of the joint. Swelling of the knee joint as well as leukocyte infiltration were enhanced in the iNOS−/− arthritic animals compared with iNOS+/+ mice with AIA. AIA‐associated leukocyte–endothelial cell interaction in synovial postcapillary venules was more pronounced in iNOS−/−, compared with iNOS+/+, arthritic mice. A strong expression of P‐selectin and VCAM‐1 was observed in the iNOS−/− arthritic mice only. Conclusion These data suggest that NO production by iNOS in vivo has antiinflammatory effects in experimental arthritis, by mediating a reduction in leukocyte adhesion and infiltration.

Endothelial iNOS versus platelet iNOS: Responsibility for the platelet/leukocyte endothelial cell interaction in murine antigen induced arthritis in vivo

“…Similar results, being controversial discussed in literature so far, have been shown in segmental intestinal ischemia/ reperfusion studies [40], leading to the conclusion of NO having an anti-inflammatory effect, also proved in studies using selective and non-selective NOS inhibition [41].…”

RANKL Stimulates Inducible Nitric-oxide Synthase Expression and Nitric Oxide Production in Developing Osteoclasts

“…Previously, NO was shown to regulate OC recruitment, formation, function, and survival in a complex, potentially biphasic, and context-dependent fashion in which NO can either stimulate (1,9,29,30,42,43) or suppress (7-13, 17-24, 43) OC formation and bone resorption. In particular, iNOS deficiency or pharmacological inhibition of NO (including by AG or L-NIL) has increased OC formation and/or bone resorption in murine, rat, and avian cell cultures (9, 10 -12, 24); stimulated OC recruitment, development, and function in association with angiogenesis in a chicken egg vascular model (13); decreased bone mass in normal or ovariectomized rats (8,25); worsened bone destruction in arthritis models (26,27); and interfered with normal bone fracture healing (28). Consistent with these studies, our present findings strongly support an inhibitory role (in this case, through a novel autocrine mode of action) for NO in restraining RANKL-induced osteoclastogenesis and bone resorption under normal physiological conditions.…”

“…Whereas low levels of NO may support osteoblast bone formation and OC-mediated bone remodeling (both basal and cytokine-induced) (9, 19 -22), high NO levels and NO-generating compounds inhibit OC formation and bone resorption and prevent bone loss, for example, in severe inflammation or estrogen-deficient animals (8, 10 -13, 17-24). Conversely, iNOS deficiency or pharmacological inhibition of NO can accelerate OC formation and bone resorption in vivo and in vitro, decrease normal bone mass, exacerbate bone destruction in arthritis or osteoporosis models, and interfere with normal fracture healing (23,(25)(26)(27)(28). On the other hand, iNOS-derived NO has been found in some studies to mediate bone loss in ovariectomized mice, interleukin-1 (IL-1)-induced OC resorption, and TNF-dependent OC survival (22,29,30).…”

Nitric oxide: a key regulator of myeloid inflammatory cell apoptosis

“…Although iNOS has been implicated in the pathogenesis of certain inflammatory diseases, such as arthritis, SLE and irritable bowel syndrome, 62 a number of studies have demonstrated a protective effect of NO against several conditions characterised by inflammation, such as glomerulonephritis, 63 acute hepatic necrosis, 64 arthritis, 65,66 endotoxaemia 64 and acute lung injury 67 in vivo (reviewed by Clancy and Abramson 62 ). Most studies attribute these effects to the wide range of general anti-inflammatory properties of NO, as reviewed by Granger and Kubes, 9 and are outwith the scope of this review.…”