title: Lack of a chondroprotective effect of cyclooxygenase 2 inhibition in a surgically induced model of osteoarthritis in mice.
abstract: OBJECTIVE
  To investigate the chondroprotective effect of cyclooxygenase 2 (COX-2) inhibition in experimental osteoarthritis (OA).
  
  
  METHODS
  The expression of prostaglandin E2 synthetic enzymes was examined by immunostaining of tibial cartilage from mice with surgically induced knee joint instability and from OA patients undergoing total knee arthroplasty. The effect of orally administered celecoxib (10 mg/kg/day and 30 mg/kg/day) or vehicle alone in mice was examined 12 weeks after the induction of OA. To investigate the involvement of COX-1 and COX-2 in OA development, we also created the model in COX-1-homozygous-knockout (Ptgs1-/-) mice and COX-2-homozygous-knockout (Ptgs2-/-) mice. OA severity was assessed using a grading system developed by our group and by the Osteoarthritis Research Society International scoring system.
  
  
  RESULTS
  In mouse and human OA cartilage, the expression of the inducible enzymes COX-2 and microsomal prostaglandin E synthase 1 (mPGES-1) was enhanced, while that of the constitutive enzymes COX-1, cytosolic PGES, and mPGES-2 was suppressed. Daily celecoxib treatment did not prevent cartilage degradation or osteophyte formation during OA development in the mouse model. Furthermore, neither Ptgs1-/- mice nor Ptgs2-/- mice exhibited any significant difference in OA development as compared to wild-type littermates.
  
  
  CONCLUSIONS
  The two COX enzymes differ in terms of regulation of their expression during OA development. Nevertheless, experiments using inhibitor and genetic deficiency demonstrated a lack of chondroprotective effect of COX-2 inhibition in the mouse surgical OA model.
authors: Sensory and Motor System Medicine, Faculty of Medicine, University of Tokyo, Tokyo, Japan.
authors: Atsushi
authors: A
authors: Fukai
authors: Satoru
authors: S
authors: Kamekura
authors: Daichi
authors: D
authors: Chikazu
authors: Takumi
authors: T
authors: Nakagawa
authors: Makoto
authors: M
authors: Hirata
authors: Taku
authors: T
authors: Saito
authors: Yoko
authors: Y
authors: Hosaka
authors: Toshiyuki
authors: T
authors: Ikeda
authors: Kozo
authors: K
authors: Nakamura
authors: Ung-il
authors: UI
authors: Chung
authors: Hiroshi
authors: H
authors: Kawaguchi
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D019645:Arthroplasty, Replacement, Knee; D002358:Cartilage, Articular / Q000187:drug effects / Q000473:pathology / Q000601:surgery; D000068579:Celecoxib; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051545:Cyclooxygenase 1 / Q000172:deficiency / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000172:deficiency / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000378:metabolism; D007593:Joint Instability / Q000188:drug therapy / Q000209:etiology; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008861:Microsomes / Q000201:enzymology; D010003:Osteoarthritis / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control; D020370:Osteoarthritis, Knee / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D000071876:Prostaglandin-E Synthases; D011720:Pyrazoles / Q000494:pharmacology*; D013264:Stifle / Q000187:drug effects / Q000473:pathology / Q000601:surgery; D013449:Sulfonamides / Q000494:pharmacology*; D013977:Tibia / Q000187:drug effects / Q000473:pathology / Q000601:surgery
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D008565:Membrane Proteins; D011720:Pyrazoles; D013449:Sulfonamides; C077623:Ptgs2 protein, mouse; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496512:Ptgs1 protein, mouse; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; C000605863:PTGES2 protein, human; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse; C000605866:Ptges2 protein, mouse; D000068579:Celecoxib