Regulation by eicosanoids of cartilagesynovialleucocyte interactions

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The suggestion has been made recently that since COX-2-derived PGE2 may underlie the inflammatory changes in joints that contribute to the destructive changes in cartilage in OA [314, 325-327]. COX-2 selective drugs (e.g., celecoxib, SC-236) appear to reverse cytokine-induced cartilage proteoglycan (PrGn) degradation and inhibition of PrGn synthesis [325-327]. Celecoxib has also been reported to counteract the depletion in hyaluronan concentration and to increase its synthesis; effects which are not observed with diclofenac [327].

In view of these observations concerning the roles of COX-2 derived PGE2 in PrGn metabolism it is useful to review the roles that eicosanoids have in the regulation of matrix metabolism in cartilage and in bone functions.

Chondrocytes produce COX-2-derived PGE2 and have EPX, EP2 and EP4 receptors for PGE2 [328-330]. PGE2 production is increased by IL-1 in chondrocytes by induction of COX-2 along with induction of nitric oxide synthase (NOS-II or iNOS) and increase in NO production [331, 332]. NO can amplify the production of PGE2 in chondrocytes of PGE2 thus indicating that there is NO-COX-2 "crosstalk" in regulation of inflammatory mediator production [333]. COX-2 is also a regulator of IL-6 production by chondrocytes [334], this effect on IL-6 production could influence acute phase protein production in the liver. IL-15 may prime TNFa production, especially in RA, that in turn drives production of IL-1, and both IL-1 and TNFa increase production of metalloproteinases [335]. The involvement of mast cells in these events is seen to be central especially in RA, but also this may be significant in OA [335].

While IL-1 and other cytokines increase chondrocyte production of LTB4 and LTC4 [336, 337] via increased activity of PLA2 [336], these cytokines reduce the synthesis of 5-lipoxygenase (5-LOX) [337]. The increased production of LTs may be a consequence of release of arachidonic acid via the transcellular movement of precursors from granulocytes in contact with chondrocytes [338] thus providing more substrate for the 5-lipoxygenase enzyme; the increased activity of this en zyme via intracellular translocation mechanisms being mediated by calcium [339], with production of anti-inflammatory lipoxins [340].

Against these proinflammatory changes are regulatory responses to the inflammatory reactions which results from (a) negative feedback by PGE2 produced from IL-1 stimulation of the PLA2 and COX-2 enzymes (which is probably a response mediated by increased cyclic AMP) [341-343], (b) the co-induction of COX-2 and NOS-II/iNOS [344-346], the stimulation of NO production by PGE2 and LTB4 [347], and the reduction of COX-2 activity by nitric oxide produced following induction of NOS-II/iNOS [344], (c) negative control of the production of IL-1 and TNFa by PGE2 against which there is enhanced production of these cytokines by LTB4, and negative controls of the T-cell mediated reactions by antiinflammatory cytokines (IL-4, IL-10, IL-15, etc.) [347-352]. The extent of involvement of T-cells in mediating osteoarthritis is probably restricted to localised inflammatory reactions in inflamed joints probably "primed" largely by fragments or decomposition products of cartilage and bone (apatite) components that initiate localised inflammation [353]. This is, in contrast, to the more extensive systemic immuno-inflammatory reactions in rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis and other related conditions [353-355].

Localised joint destruction in OA involve (a) inflammatory reactions in synovial tissues that may be initiated by cartilage and bone fragments and decomposition products constituting neoantigens [356], (b) regional vascular ischaemia leading to production of tissue destructive oxyradicals and promoted by local arteriosclerosis in which there is restricted blood flow to both synovial tissues and sub-chondral bone and vascular inflammation [357, 358] which may also be initiated by "foam" cells or activated macrophages in the vascular wall, (c) infiltration and activation of neutrophils (see section on "Nimesulide and neutrophil functional responses", p. 173) with accompanying complement activation [233], (d) destruction and degradation of cartilage and involvement of associated sub-chondrial cells and bone driven by synovial-leucocyte interactions, the production of metalloproteinases and other proteases stimulated by proinflammatory cy-tokines [358, 359], (e) inhibition of the synthesis of proteoglycan and collagen components of cartilage by IL-1 and TNFa by cytokines [359, 360], (f) regional T- and B-cell activation leading to further promotion of the immune-based reaction in the OA synarthrodal joints [361-363], (g) changes in the osteoblasts and osteoclasts of subchondral bone leading to bone lysis [364] and (h) alteration in the production of growth factors some of which may be important in cartilage and bone repair [365].

Similar increases in eicosanoids initiated by IL-4, TNFa, g-IFN and other proinflammatory cytokines occur with synovial cells, the synovial A-cell and infiltrated and activated macrophages [351] as well as from polymorphonuclear neutrophil leucocytes (see also early section on "Nimesulide and neutrophil functional responses", p. 173). The proportion of the principal COX-2 and 5-, 12- and 15-

LOX products (PGE2, LTB4, LTC4 and lipoxins) that mediate the major part of synovial-cartilage inflammatory changes that are produced in the articular cartilage and synovial capsule will depend on the extent of the cytokine- and other inflammogenic stimuli, and the type and extent of T-cell immune stimulus in the inflamed synovium, the production of sPLA2, COX-2 and 5-LOX enzymes in different cells in the synarthrodal region.

Diagrammatic representations of the inflammatory events in the synarthrodal joints in OA can be seen in Figures 16-18 showing:

• The anatomic changes in the synovial capsule featuring synovitis and hyperpla-sia, ischaemia and changes in subchondral bone and cartilage in synarthrodal joints in OA (Fig. 16).

• The cellular events in the cartilage-synovial-leucocyte interactions involving production of inflammatory mediators and oxyradicals, destruction of matrix macromolecules by activated or cytokine-mediated synthesis of metallopro-teinases and the underplay of cytokine-eicosanoid interactions that mediate these destructive events (Figs 17 and 18). These figures also show the principal sites of action of nimesulide (NIM), the details of which will follow later.

Figure 16

Synarthrodal joint showing areas of cartilage and bone destruction in arthritis and the associated involvement of synovitis and vascular changes. From Burkhardt and Ghosh (1987) [299]. Redrawn and reproduced with permission of the publishers of Seminars in Arthritis and Rheumatism.

Figure 16

Synarthrodal joint showing areas of cartilage and bone destruction in arthritis and the associated involvement of synovitis and vascular changes. From Burkhardt and Ghosh (1987) [299]. Redrawn and reproduced with permission of the publishers of Seminars in Arthritis and Rheumatism.

Synovial cells

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