Evidence for a direct role of cyclo-oxygenase 2 in implant wear debris-induced osteolysis

Aseptic loosening is a major complication of prosthetic joint surgery and i s manifested as chronic inflammation,, pain, and osteolysis at the bone imp lant interface. The osteolysis is believed to be driven by a host inflammat ory response to wear debris generated from the implant. In our current stud y, we use a selective inhibitor (celecoxib) of cyclo-oxygenase 2 (COX-2) an d mice that lack either COX-1 (COX-1-/-) or COX-2 (COX-2-/-) to show that C OX-2, but not COX-1, plays an important role in wear debris-induced osteoly sis. Titanium (Ti) wear debris was implanted surgically onto the calvaria o f 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. CO X-2 and prostaglandin E-2 (PGE(2)) production increased in the calvaria and inflammatory tissue overlying it after Ti implantation. Celecoxib (25 mg/k g per day) significantly reduced the inflammation, the local PGE, productio n, and osteolysis, In comparison with wild-type and COX-1-/- mice, COX-2-/- mice implanted with Ti had a significantly reduced calvarial bone resorpti on response, independent of the inflammatory response, and significantly fe wer osteoclasts were formed from cultures of their bone marrow cells. These results provide direct evidence that COX-2 is an important mediator of wea r debris-induced osteolysis and suggests that COX-2 inhibitors are potentia l therapeutic agents for the prevention of wear debris-induced osteolysis.