title: PGE2 and IL-6 production by fibroblasts in response to titanium wear debris particles is mediated through a Cox-2 dependent pathway.
abstract: Aseptic loosening of orthopaedic implants is precipitated by wear debris-induced osteolysis. Central to this process are the pro-inflammatory mediators that are produced in response to wear by the fibroblastic cells, which comprise the majority of periprosthetic membranes. Since this pro-inflammatory cascade is mediated by a plethora of factors with redundant functions, it is imperative to establish a hierarchy. Two well-known fibroblast derived pro-inflammatory factors that stimulate wear debris-induced osteoclastic resorption are prostaglandin E2 (PGE2) and IL-6. However, their relationship to each other in this process is poorly defined. Here we show immunohistochemistry of retrieval membranes indicating that COX-2 is the principal cyclooxygenase responsible for PGE2 production in fibroblasts around failed implants. We also performed in vitro experiments with fibroblasts derived from wild-type (WT), COX-1 (-/-) and COX-2 (-/-) mice, which demonstrated that COX-2 is required for Ti wear debris-induced PGE2 production. Interestingly, COX-2 was also required for IL-6 production in these assays, which could be rescued by the addition of exogenous PGE2 (10(-6) M). Pharmacology studies that utilized the COX-1 selective inhibitor SC 560, the COX-2 selective inhibitor celecoxib, and the nonselective COX inhibitor indomethacin confirmed these results. Taken together, these results indicate that selective inhibition of prostaglandin signaling could favorably impact aseptic loosening beyond its direct effects on PGE2 synthesis, in that it inhibits downstream pro-inflammatory/pro-osteoclastic cytokine production.
authors.affiliation: The Department of Orthopaedics, University of Rochester Medical Center, Center for Musculoskeletal Research, 601 Elmwood Avenue, Box 665, Rochester, NY 14642, USA.
authors.forename: Susan V
authors.initials: SV
authors.lastname: Bukata
authors.forename: Jill
authors.initials: J
authors.lastname: Gelinas
authors.forename: Xiaochao
authors.initials: X
authors.lastname: Wei
authors.forename: Randy N
authors.initials: RN
authors.lastname: Rosier
authors.forename: J Edward
authors.initials: JE
authors.lastname: Puzas
authors.forename: Xinping
authors.initials: X
authors.lastname: Zhang
authors.forename: Edward M
authors.initials: EM
authors.lastname: Schwarz
authors.forename: Xiao-yu R
authors.initials: XY
authors.lastname: Song
authors.forename: Don E
authors.initials: DE
authors.lastname: Griswold
authors.forename: Regis J
authors.initials: RJ
authors.lastname: O'Keefe
mesh_terms: D000818:Animals; D002460:Cell Line; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D066298:In Vitro Techniques; D015850:Interleukin-6 / Q000378:metabolism*; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008808:Mice, Inbred CBA; D010014:Osteolysis; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism*; D011475:Prosthesis Failure; D014025:Titanium / Q000494:pharmacology*
chemical_list: D015850:Interleukin-6; D007527:Isoenzymes; D014025:Titanium; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone