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From observations in animal models of OA there is substantial evidence that NSAIDs are toxic to articular cartilage. Drs. Marshall J. Palmoski and Kenneth D. Brandt from the Indiana University School of Medicine published several research papers showing that NSAIDs suppress chondrocyte proteoglycan (PRG) synthesis. Prior to these studies they had already shown that salicylate (aspirin), the drug most commonly employed in the treatment of OA at the time, reduced PRG synthesis in cultures of normal articular cartilage by about 30% and in cultures of OA cartilage by up to 99% at levels achieved in the serum of patients treated with salicylate.⁵⁰ They also showed that salicylate (aspirin) accelerated the development of structure damage in the OA joint in the canine cruciate-deficient model or that caused by immobilization, and resulted in more severe pathology than that seen in the OA knees of dogs not treated with the drug.^51-53 As more clinicians started using ibuprofen and other NSAIDs, instead of aspirin for OA, Drs. Palmoski and Brandt studied the effects these drugs had on canine articular cartilage. Specifically they found that fenoprofen and ibuprofen inhibited net PRG synthesis in a concentration-dependent fashion. At concentrations in the culture medium comparable to plasma concentrations seen in patients after oral administration of NSAIDs in humans, net PRG synthesis in the presence of these drugs averaged 72% and 86% of the control values, respectively (P<0.01).^54-56 (See Figure 10.)

In another study on canine articular cartilage, these researchers found that the inhibitory effect of the NSAID indomethacin was greater when the articular cartilage was depleted of glycosaminoglycans.⁵⁷ In other words, there is a greater inhibition of PRG synthesis in osteoarthritic cartilage than normal cartilage. Other researchers have confirmed these findings that NSAIDs consistently suppress proteoglycan and glycosaminoglycan synthesis.^58-60 This depletion of matrix proteoglycans has been shown to be one cause of the increased degeneration of cartilage chondrocytes from the use of NSAIDs.⁶¹ Taken to the extreme, one researcher put it this way, “…depending on dose and at concentrations that in many cases correspond to therapeutic plasma levels, these drugs may lead to a pronounced reduction or complete blockade of synthesis of the proteoglycans and collagen of the cartilage matrix.” They went on to say that the medications can “induce progressive joint degeneration within three to four months.”62
Animal studies have also shown the effects of NSAIDs on proliferation, cell cycle kinetics, cytotoxicity, and cell death of chondrocytes. In one study the NSAIDs indomethacin, ketorolac, diclofenac, piroxicam, and celecoxib inhibited thymidine incorporation of chondrocytes at therapeutic concentrations. NSAIDs also arrested chondrocytes in their cell cycles, thus inhibiting chondrocyte cell replication. Upon 24 hour exposure to indomethacin, ketorolac, diclofenac, and piroxicam, chondrocyte cell death (both apoptosis and necrosis) was induced in cell cultures.⁶³ One mechanism by which NSAIDs are toxic to chondrocytes is by inhibiting PGE2 synthesis by chondrocytes.⁶⁴ PGE2 elicits differentiation of chondrocytes and is an important contributor to cartilage formation and promotes DNA and matrix synthesis in chondrocytes.^{65, 66} PGE2 has a growth stimulatory effect on chondrocytes, thereby increasing chondrocyte DNA synthesis.^{67, 68} NSAIDs inhibit the enzyme cyclooxygenase which is responsible for PGE2 release in chondrocytes.⁶⁹