title: Evidence for a direct role of cyclo-oxygenase 2 in implant wear debris-induced osteolysis.
abstract: 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.
authors.affiliation: Department of Orthopedics, University of Rochester School of Medicine and Dentistry, New York, USA.
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.forename: S G
authors.initials: SG
authors.lastname: Morham
authors.forename: R
authors.initials: R
authors.lastname: Langenbach
authors.forename: D A
authors.initials: DA
authors.lastname: Young
authors.forename: L
authors.initials: L
authors.lastname: Xing
authors.forename: B F
authors.initials: BF
authors.lastname: Boyce
authors.forename: E J
authors.initials: EJ
authors.lastname: Puzas
authors.forename: R N
authors.initials: RN
authors.lastname: Rosier
authors.forename: R J
authors.initials: RJ
authors.lastname: O'Keefe
authors.forename: E M
authors.initials: EM
authors.lastname: Schwarz
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000209:etiology; D000068579:Celecoxib; D002478:Cells, Cultured / Q000187:drug effects; D003433:Crosses, Genetic; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000096:biosynthesis; D005260:Female; D007375:Interleukin-1 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008262:Macrophage Activation; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D010010:Osteoclasts / Q000473:pathology; D010014:Osteolysis / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D011451:Prostaglandin-Endoperoxide Synthases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D019736:Prostheses and Implants; D011475:Prosthesis Failure; D011720:Pyrazoles; D012886:Skull; D013449:Sulfonamides / Q000494:pharmacology; D014025:Titanium; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007375:Interleukin-1; D015850:Interleukin-6; D007527:Isoenzymes; D008565:Membrane Proteins; D011720:Pyrazoles; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; D014025:Titanium; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse; D000068579:Celecoxib; D015232:Dinoprostone