COX-1 Important in Autoimmune Arthritis
Prostaglandins are mediators that contribute to the onset and progression of pathologic inflammation. High concentrations of various prostaglandins are present in the joint fluid of people with rheumatoid arthritis and other inflammatory joint diseases.
Cyclooxygenase (COX) enzymes are necessary for the production of prostaglandins. Traditionally, COX-1 has been considered to be involved in a wide variety of bodily functions, whereas COX-2 has been considered the main contributor of prostaglandin synthesis associated with inflammation. Classic nonsteroidal anti-inflammatory drugs (NSAIDs) block the production of both COX-1 and COX-2. These drugs help reduce inflammation, but they can also have effects throughout the body, most notably in the gastrointestinal tract. NSAIDs that specifically block COX-2 were developed, and these proved to be safer for the stomach, but they had unexpected effects on the cardiovascular system.
What Problem Was Studied?
To clarify the roles of prostaglandins and COX enzymes in inflammatory arthritis, and to understand how COX inhibitors can be used to treat the disease, a series of experiments was developed using a mouse model of inflammatory arthritis. Arthritis Foundation-funded scientists Mei Chen, MD, PhD, Eric Boilard, PhD, and David M. Lee, MD, PhD, of Brigham and Women’s Hospital, Harvard Medical School in Boston, and their colleagues examined the contribution of prostaglandins to both the induction and perpetuation of arthritis in these mice.
What Was Done in the Study?
The serum (liquid portion of blood) from arthritic mice was administered to other mice, in which arthritis was then induced. Prostaglandin levels in the joints of those mice were determined. A potent inhibitor of both COX-1 and COX-2 was administered to some mice before arthritis provocation and to some mice after arthritis had developed. Mice that were genetically altered to be unable to produce the COX-1 enzyme were administered the serum; likewise, mice that were unable to produce the COX-2 enzyme were administered the serum. Medications that specifically inhibited COX-1 or COX-2 were given to the mice before and after the induction of arthritis.
What Were the Study Results?
The study showed that prostaglandins definitely contribute to joint inflammation in this particular model of inflammatory arthritis. This was proven by the fact that by giving the mice a potent NSAID that blocks prostaglandin synthesis, arthritis would not develop. The experiment using genetically altered mice proved that COX-1 was primarily responsible for the prostaglandin synthesis that led to joint inflammation. This finding was further supported with the experiments using chemicals that specifically inhibited COX-1 or COX-2. The scientists determined that in this particular model of inflammatory arthritis, COX-1 was necessary for the initiation and continuation of arthritis and COX-2 was dispensable.
In studying the prostaglandin levels in the joints during the various experiments, the research team determined that perhaps prostacyclin derived from the action of the COX-1 enzyme is related to joint inflammation, but that prostacyclin derived from the action of the COX-2 enzyme is not. Prostacyclin is a prostaglandin that is active in the cardiovascular system.
What Does This Mean for People With Arthritis?
In the big picture, the results of this study indicate that the way scientists have been looking at prostaglandins, COX enzymes and the development of inflammation may have been slightly off. Their findings indicate that inflammatory arthritis may proceed via multiple, interacting pathways of prostaglandin synthesis, and that different COX enzymes are active in different pathways.
Because blocking the production of prostacyclin derived from COX-2 has been associated with cardiovascular risk, the research team hypothesizes, “Sparing COX-2–dependent prostacyclin production may confer cardiovascular protection to arthritis patients, a population with demonstrated increased cardiovascular risk.”
The team further concludes, “The identification of predominant roles for COX-1 and discrete prostaglandin species suggests that antagonism of specific prostaglandin species may be an effective therapeutic strategy if it can be achieved without the limiting toxicity that has thus far plagued the use of such inhibitors clinically.”
Chen M, Boilard E, Nigrovic PA, et al. Predominance of cyclooxygenase 1 over cyclooxygenase 2 in the generation of proinflammatory prostaglandins in autoantibody-driven K/BxN serum-transfer arthritis. Arthritis Rheum 2008;58:1354-65.
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