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.

CONCLUSION:

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: Atsushi Fukai, Satoru Kamekura, Daichi Chikazu, Takumi Nakagawa, Makoto Hirata, Taku Saito, Yoko Hosaka, Toshiyuki Ikeda, Kozo Nakamura, Ung-il Chung, Hiroshi Kawaguchi
• Journal: Arthritis and rheumatism (Arthritis Rheum) Vol. 64 Issue 1 Pg. 198-203 (Jan 2012) ISSN: 1529-0131 [Electronic] United States
• PMID: 21905007 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 by the American College of Rheumatology.

Chemical References

• Cyclooxygenase 2 Inhibitors
• Membrane Proteins
• Pyrazoles
• Sulfonamides
• Ptgs2 protein, mouse
• Cyclooxygenase 1
• Cyclooxygenase 2
• Ptgs1 protein, mouse
• Intramolecular Oxidoreductases
• PTGES protein, human
• PTGES2 protein, human
• Prostaglandin-E Synthases
• Ptges protein, mouse
• Ptges2 protein, mouse
• Celecoxib

Topics

• Administration, Oral
• Animals
• Arthritis, Experimental (drug therapy, enzymology, pathology)
• Arthroplasty, Replacement, Knee
• Cartilage, Articular (drug effects, pathology, surgery)
• Celecoxib
• Chondrocytes (drug effects, metabolism, pathology)
• Cyclooxygenase 1 (deficiency, metabolism)
• Cyclooxygenase 2 (deficiency, metabolism)
• Cyclooxygenase 2 Inhibitors (pharmacology)
• Female
• Humans
• Intramolecular Oxidoreductases (metabolism)
• Joint Instability (drug therapy, etiology)
• Male
• Membrane Proteins (deficiency, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Microsomes (enzymology)
• Osteoarthritis (enzymology, pathology, prevention & control)
• Osteoarthritis, Knee (drug therapy, enzymology, pathology)
• Prostaglandin-E Synthases
• Pyrazoles (pharmacology)
• Stifle (drug effects, pathology, surgery)
• Sulfonamides (pharmacology)
• Tibia (drug effects, pathology, surgery)