Cyclooxygenase inhibition lowers prostaglandin E2 release from articular cartilage and reduces apoptosis but not proteoglycan degradation following an impact load in vitro.
This study investigated the release of prostaglandin E2 (PGE2) from cartilage following an impact load in vitro and the possible chondroprotective effect of cyclooxygenase-2 (COX-2) inhibition using non-steroidal anti-inflammatory drugs (NSAIDs). Explants of human articular cartilage were subjected to a single impact load in a drop tower, and then cultured for 6 days in the presence of either a selective COX-2 inhibitor (celecoxib; 0.01, 0.1, 1.0 and 10 microM) or a non-selective COX inhibitor (indomethacin; 0.1 and 10 microM). The concentrations of PGE2 and glycosaminoglycans (GAGs), a measure of cartilage breakdown, were measured in the explant culture medium at 3 and 6 days post-impact. Apoptotic cell death was measured in frozen explant sections by the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling (TUNEL) method. PGE2 levels were increased by more than 20-fold in the medium of explants at both 3 (p = 0.012) and 6 days (p = 0.004) following impact, compared with unloaded controls. In the presence of celecoxib and indomethacin, the PGE2 levels were reduced in a dose-related manner. These inhibitors, however, had no effect in reducing the impact-induced release of GAGs from the cartilage matrix. Addition of celecoxib and indomethacin significantly reduced the number of trauma-induced apoptotic chondrocytes in cartilage explant sections. In this study, a marked increase in PGE2 was measured in the medium following an impact load on articular cartilage, which was abolished by the selective COX-2 inhibitor, celecoxib, and non-selective indomethacin. These inhibitors reduced chondrocyte apoptosis but no change was observed in the release of GAGs from the explants, suggesting that the COX/PGE2 pathway is not directly responsible for cartilage breakdown following traumatic injury. Our in vitro study demonstrates that it is unlikely that COX-2 inhibition alone would slow down or prevent the development of secondary osteoarthritis.
Jeffrey
Janet E
JE
Department of Orthopaedic Surgery, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen, AB25 2ZD, UK. j.e.jeffrey@abdn.ac.uk
Aspden
Richard M
RM
D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002358:Cartilage, Articular / Q000187:drug effects* / Q000293:injuries / Q000378:metabolism* / Q000473:pathology; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000096:biosynthesis*; D006025:Glycosaminoglycans / Q000378:metabolism; D006801:Humans; D008875:Middle Aged; D010003:Osteoarthritis / Q000209:etiology / Q000517:prevention & control; D011509:Proteoglycans / Q000378:metabolism*; D013314:Stress, Mechanical; D046509:Tissue Culture Techniques
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D006025:Glycosaminoglycans; D011509:Proteoglycans; D015232:Dinoprostone