Figure 1. Both nonsteroidal anti-inflammatory drugs (NSAIDs) and omega-3 fatty acids can reduce the production of eicosanoids
generated via the cyclooxygenase (COX) pathway. In addition, by competitive inhibition, omega-3 fatty acids can reduce the
production of proinflammatory mediators produced by 5-lipoxygenase.18,33
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In addition to PGE2, other eicosanoids are produced from arachidonic acid via the COX or 5-lipoxygenase (LOX) enzymes; these eicosanoids include
thromboxane A2 (TXA2) and leukotriene B4 (LTB4) and are involved in osteoarthritis pathogenesis (Figure 1).33 The activities of these enzymes and resulting eicosanoids are increased in osteoarthritis: osteoarthritic cartilage spontaneously
releases 50 times more PGE2 compared with normal cartilage.18,24,34 LTB4 promotes the synthesis and release of IL-1 and TNF-α. Further, LTB4 is a potent chemotactic agent and can increase neutrophil-induced damage to local tissues.33,35 TXA2 stimulates monocytes to release TNF-α and IL-1, which subsequently promote MMP production and joint destruction.35 PGE2 promotes local inflammation and pain. An increase in PGE2 concentration has been shown to correlate with lameness and pain in dogs with osteoarthritis.36 PGE2 can promote osteoclastic bone resorption, increased type II collagen destruction, and proteoglycans loss.23,34,37 PGE2 stimulates IL-6 release from fibroblasts, and it also sensitizes chondrocytes to free radical nitric oxide effects.33,37 COX-2 enzyme inhibition decreases PGE2 and IL-6 concentrations.37,38
Altering gene-expression changes in osteoarthritis
As you can see, this inflammatory cycle is self-perpetuating, with inflammatory mediators subsequently stimulating other mediators
that further the cycle. To break the cycle, one effective target has been inhibition of COX-2 enzyme-produced eicosanoids,
especially PGE2. Eicosapentaenoic acid, a long-chain omega-3 fatty acid, can alter the COX-derived eicosanoids. When eicosapentaenoic acid
replaces part of the arachidonic acid in cell membranes, eicosapentaenoic acid may be used instead of arachidonic acid for
eicosanoid production, resulting in a different and less inflammatory set of compounds (e.g., PGE3, TXA3, and LTB5, instead of PGE2, TXA2, and LTB4). (See Figure 1.)
Eicosapentaenoic acid has been analyzed for its ability to modulate inflammatory mediators in osteoarthritis, using both in
vitro and in vivo studies. Arthritic dogs fed a diet enriched with eicosapentaenoic acid had decreased MMP-2 and MMP-9 concentrations and increased
TIMP-2 concentrations in synovial fluid, as well as decreased plasma PGE2.39 Likewise, in vitro studies have shown MMP expression decreases in canine arthritic cartilage in response to eicosapentaenoic
acid (R.P. Middleton; S.S. Hannah: Unpublished data, 2004).
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