Suppression of Adjuvant-Induced Arthritic Bone Destruction by Cyclooxygenase-2 Selective Agents With and Without Inhibitory Potency Against Carbonic Anhydrase II

Abstract

In vitro assays revealed that COX-2 inhibitors with CA II inhibitory potency suppressed both differentiation and activity of osteoclasts, whereas that without the potency reduced only osteoclast differentiation. However, all COX-2 inhibitors similarly suppressed bone destruction in adjuvant-induced arthritic rats, indicating that suppression of osteoclast differentiation is more effective than that of osteoclast activity for the treatment.Introduction: Cyclooxygenase (COX)-2 and carbonic anhydrase II (CA II) are known to play important roles in the differentiation of osteoclasts and the activity of mature osteoclasts, respectively. Because several COX-2 selective agents were recently found to possess an inhibitory potency against CA II, this study compared the bone sparing effects of COX-2 selective agents with and without the CA II inhibitory potency. Materials and Methods: Osteoclast differentiation was determined by the mouse co-culture system of osteoblasts and bone marrow cells, and mature osteoclast activity was measured by the pit area on a dentine slice resorbed by osteoclasts generated and isolated from bone marrow cells. In vivo effects on arthritic bone destruction were determined by radiological and histological analyses of hind-paws of adjuvant-induced arthritic (AIA) rats. Results: CA II was expressed predominantly in mature osteoclasts, but not in the precursors. CA II activity was inhibited by sulfonamide-type COX-2 selective agents celecoxib and JTE-522 similarly to a CA II inhibitor acetazolamide, but not by a methylsulfone-type COX-2 inhibitor rofecoxib. In vitro assays clearly revealed that celecoxib and JTE-522 suppressed both differentiation and activity of osteoclasts, whereas rofecoxib and acetazolamide suppressed only osteoclast differentiation and activation, respectively. However, bone destruction in AIA rats was potently and similarly suppressed by all COX-2 selective agents whether with or without CA II inhibitory potency, although only moderately by acetazolamide. Conclusions: Suppression of osteoclast differentiation by COX-2 inhibition is more effective than suppression of mature osteoclast activity by CA II inhibition for the treatment of arthritic bone destruction.

Dual Carbonic Anhydrase - Cyclooxygenase-2 Inhibitors

“…The authors evidenced that CA II was expressed in CA II predominantly in mature osteoclasts, but not in the precursors. In agreement with the results discussed above, the activity of CA II expressed in osteoclasts was inhibited by sulfonamide-type COX-2 selective agents celecoxib similarly to CA II inhibitor acetazolamide, but not by a methylsulfone-type COX-2 inhibitor rofecoxib [19].…”

Titanium particles stimulate COX-2 expression in synovial fibroblasts through an oxidative stress-induced, calpain-dependent, NF-κB pathway

“…Previously, we showed that mice deficient in COX-2 have reduced inflammatory bone loss following implantation of Ti particles onto the calvaria, and we demonstrated that synovial fibroblasts produce RANKL following particle stimulation (56,58). More recently, COX-2 inhibition reduced both inflammation and local bone loss in the hindfoot of rats with adjuvantinduced arthritis (22). The current findings are consistent with these prior reports and establish the importance of the NF-B/ COX-2 signaling pathway during RANKL induction in FLS.…”

Etodolac, a Cyclooxygenase-2 Inhibitor, Attenuates Paclitaxel-Induced Peripheral Neuropathy in a Mouse Model of Mechanical Allodynia

“…Etodolac attenuated paclitaxel-induced mechanical allodynia in this model, but the COX inhibitors indomethacin, diclofenac, and celecoxib did not. The dosage of each COX inhibitor was chosen to be sufficient to produce anti-inflammatory effects in our previous study ) and in other studies (Inoue et al, 1991;Katagiri et al, 2006) in rodent models. The antiallodynic effect of etodolac was cumulative, and after 2 weeks' administration it was observed at the preadministration point.…”