• Failed Rotator Cuff Surgery: Can Prolotherapy Help?
  May 22, 2012
• Multiple Painful Joints Require Comprehensive Approach
  May 21, 2012
• Knee and Hip Osteoarthritis in Older Athletes
  May 20, 2012
• Complete Blog List

One way in which NSAIDs stop the chondrocytes from repairing themselves is by the inhibition of the synthesis of Prostaglandin E2 (PGE2). Prostaglandins (PG) are produced by most human cell types (including chondrocytes) and have a variety of physiologic functions. PG synthesis is initiated by the mobilization of arachidonic acid from cell membrane phospholipids as a result of the enzyme phospholipase A2. The enzyme cyclooxygenase along with other enzymes converts arachidonic acid to five primary prostaglandins: PGD2, PGE2, PGI2 (Prostacyclin), PGF2a, and TXA2 (thomboxane). (See Figure 13.) These PGs have a variety of functions including the mediation of inflammation, calcium movement, sensitization of spinal neurons to pain, blood clotting, blood pressure, circulation, control of blood flow in kidneys, hormone regulation, protection of gastrointestinal lining, and the control of cell growth.^{80, 81} Chondrocytes and synovial fibroblasts produce PGE2. PGE2 levels are increased to an impact load on articular cartilage or during cartilage degeneration.^{82, 83} PGE2 is reported to have anabolic effects on cartilage: increasing proteoglycan and DNA and collagen synthesis,^{84, 85} stimulating proliferation and proteoglycan aggrecan synthesis,^{86, 87} and, at low concentrations, stimulating type II collagen synthesis.⁸⁸

Human chondrocytes express two forms of the cyclooxygenase enzyme, known as the COX-1 and COX-2 isoforms. Unstimulated human chondrocytes do not contain detectable COX-2.⁸⁹ COX-1 is present in most cells under physiological conditions, whereas COX-2 is induced by some cytokines presumably in pathological conditions such as joint trauma, degeneration, or osteoarthritis.^{90, 91} Put another way, COX-2 is undetectable in most normal tissues, is an inducible enzyme, becoming abundant in activated macrophages (immune cells) and other cells at sites of inflammation. Prostaglandins, whose synthesis involves COX-1, are responsible for maintenance and protection of the gastrointestinal tract, while prostaglandins, whose synthesis involves COX-2, are responsible for inflammation and pain. One of the main prostaglandins involved in this inflammatory reaction is PGE2. Researchers have shown that the PGE2 levels correlate with the amount of COX-2 expression in chondrocytes.⁹² (See Figure 14.) Also well established is that this PGE2 release can easily be inhibited by the use of NSAIDs.^{93, 94} (See Figure 15.) Since the over expression of the COX-2 protein plays an important role in many pathophysiologic states, including inflammation, cancer, angiogenesis, Alzheimer’s disease, and several forms of inflammatory arthritis, NSAIDs especially those that inhibit COX-2, are used for many of these conditions. In regard to joint inflammation, one author notes, “…by inhibiting joint conditions, they (NSAIDs) may indirectly be beneficial to cartilage, specifically when inflammation is primary in the cause of cartilage damage, as in the case for rheumatoid arthritis.” However, in OA, in which inflammation may contribute to but is not primarily responsible for cartilage damage, adverse direct effects of NSAIDs on cartilage with long-term treatment may have an important impact on long-term outcome.”⁹⁴ In other words PGE2 can exert catabolic or anabolic effects depending on the microenvironment.⁹⁵

Since normal articular chondrocytes produce very little PGE2 and osteoarthritic chondrocytes produce a lot of it through the COX-2 enzyme, it would make sense from a traditional medical point of view to attack arthritis pain from this angle. This is especially true since the over expression of the COX-2 protein (and thus increased PGE2 levels) plays an important role in many pathophysiolgic states, including systemic inflammation, fever, cancer, angiogenesis, Alzheimer’s disease, and inflammatory arthritis.⁹⁶ Yes, in certain conditions inflammation is harmful, but it is a big leap to assume everywhere there is PGE2 it is harming tissue. The articular chondrocytes make PGE2 in response to injury to stimulate healing. Osteoarthritic cartilage spontaneously releases PGE2 in levels at least 50-fold higher than normal cartilage and 18-fold higher than normal cartilage stimulated with cytokines and endotoxin.^97-100 The inflammation that occurs through PGE2 when a normal or osteoarthritic joint is injured is the body’s immune system response to try and get the joint injury repaired.¹⁰¹ When a person uses medications that block this response, while pain may be improved, the repair mechanisms for the joint are inhibited. The long-term consequences, of course can be an acceleration of the degenerative osteoarthritic process. (See Figure 16.) Long-term NSAID treatment not only blocks PGE2 production by direct inhibition of COX-2 activity but by down-regulating COX-2 synthesis.¹⁰²