Evidence for a Direct Role of Cyclo‐Oxygenase 2 in Implant Wear Debris‐Induced Osteolysis

• Published in: Journal of bone and mineral research Vol. 16; no. 4; pp. 660 - 670
• Main Authors: Zhang, Xinping, Morham, Scott G., Langenbach, Robert, Young, Donald A., Xing, Lianping, Boyce, Brendan F., Puzas, Edward J., Rosier, Randy N., O'Keefe, Regis J., Schwarz, Edward M.
• Format: Journal Article
• Language: English
• Published: Washington, DC John Wiley and Sons and The American Society for Bone and Mineral Research (ASBMR) 01.04.2001; American Society for Bone and Mineral Research
• Subjects: Animals; aseptic loosening; Biological and medical sciences; Bone Resorption - etiology; Bones, joints and connective tissue. Antiinflammatory agents; Celecoxib; Cells, Cultured - drug effects; Crosses, Genetic; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors - pharmacology; cyclo‐oxygenase 2; Dinoprostone - biosynthesis; Female; inflammation; Interleukin-1 - biosynthesis; Interleukin-6 - biosynthesis; Isoenzymes - antagonists & inhibitors; Isoenzymes - deficiency; Isoenzymes - genetics; Isoenzymes - physiology; Macrophage Activation; Medical sciences; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Knockout; Orthopedic surgery; Osteoclasts - pathology; osteolysis; Osteolysis - enzymology; Osteolysis - etiology; Osteolysis - pathology; Pharmacology. Drug treatments; prostaglandin E2; prostaglandin G/H synthase; Prostaglandin-Endoperoxide Synthases - deficiency; Prostaglandin-Endoperoxide Synthases - genetics; Prostaglandin-Endoperoxide Synthases - physiology; Prostheses and Implants; Prosthesis Failure; Pyrazoles; Skull; Sulfonamides - pharmacology; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Titanium; Tumor Necrosis Factor-alpha - biosynthesis; Prostaglandin-endoperoxide synthase; Wear particle; Prosthesis; Diseases of the osteoarticular system; Prostaglandin E2; Osteolysis; Osteoarticular system; Prevention; Eicosanoid; Complication; Bone defect; Enzyme; Arachidonic acid derivatives; Rodentia; Enzyme inhibitor; Resorption; Inflammation; Joint; Vertebrata; Calvaria; Mammalia; Orthopedic surgery; Mouse; Animal; Oxidoreductases; Bone
• ISSN: 0884-0431; 1523-4681
• DOI: 10.1359/jbmr.2001.16.4.660

Aseptic loosening is a major complication of prosthetic joint surgery and is manifested as chronic inflammation, pain, and osteolysis at the bone implant interface. The osteolysis is believed to be driven by a host inflammatory response to wear debris generated from the implant. In our current study, we use a selective inhibitor (celecoxib) of cyclo‐oxygenase 2 (COX‐2) and mice that lack either COX‐1 (COX‐1−/−) or COX‐2 (COX‐2−/−) to show that COX‐2, but not COX‐1, plays an important role in wear debris‐induced osteolysis. Titanium (Ti) wear debris was implanted surgically onto the calvaria of the mice. An intense inflammatory reaction and extensive bone resorption, which closely resembles that observed in patients with aseptic loosening, developed within 10 days of implantation in wild‐type and COX‐1−/− mice. COX‐2 and prostaglandin E2 (PGE2) production increased in the calvaria and inflammatory tissue overlying it after Ti implantation. Celecoxib (25 mg/kg per day) significantly reduced the inflammation, the local PGE2 production, and osteolysis. In comparison with wild‐type and COX‐1−/− mice, COX‐2−/− mice implanted with Ti had a significantly reduced calvarial bone resorption response, independent of the inflammatory response, and significantly fewer osteoclasts were formed from cultures of their bone marrow cells. These results provide direct evidence that COX‐2 is an important mediator of wear debris‐induced osteolysis and suggests that COX‐2 inhibitors are potential therapeutic agents for the prevention of wear debris‐induced osteolysis.