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 E 2 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.

CCL2 and CCR2 regulate pain-related behaviour and early gene expression in post-traumatic murine osteoarthritis but contribute little to chondropathy

“…Several of these have been examined in knockout studies in vivo . For example, the Ptgs 1/2 double knockout mouse did not have altered chondropathy scores following DMM 5 , whereas IL6 has a conflicting role in disease; both an increase in disease with age has been observed as well as decreased disease in experimental OA (induced by DMM) in IL6 knockout mice6, 7. Mmp3 knockout mice develop a small increase in disease following surgical destabilisation 4 indicating a neutral or mildly protective role in the joint.…”

Emerging regulators of the inflammatory process in osteoarthritis

“…These treatments include glucocorticosteroids, NSAIDs and coxibs (100), and other FDA-approved medical treatments such as intra-articular hyaluronan (101,102). Moreover, certain nutraceuticals can modulate proteostasis or inflammatory processes, or both (102–104).…”

The Role of Innate Immunity in Osteoarthritis: When Our First Line of Defense Goes On the Offensive

“…Specifically, can slowing the inflammatory response lead to either symptomatic improvement or halt the progression in OA? Previous animal knockout models for COX-1 and COX-2 (75) and IL-1β and ICE have failed to show any chondroprotective effect (76) (and may have lead to increased disease). Knockout models are not always the most informative as it is difficult to ascertain any possible off-target effects (as illustrated by the previous study by Fukai et al (75)).…”

“…Previous animal knockout models for COX-1 and COX-2 (75) and IL-1β and ICE have failed to show any chondroprotective effect (76) (and may have lead to increased disease). Knockout models are not always the most informative as it is difficult to ascertain any possible off-target effects (as illustrated by the previous study by Fukai et al (75)). Instead, are there other in vivo study designs that provide a more realistic but accelerated model for OA?…”