The flurbiprofen derivatives HCT1026 and HCT1027 inhibit bone resorption by a mechanism independent of COX inhibition and nitric oxide production

Bone
Aymen I IdrisRob J van't Hof

Abstract

Prostaglandins and nitric oxide both modulate bone resorption and bone formation. We previously reported that a nitrosylated derivative of flurbiprofen, termed HCT1026, exerted inhibitory effects on osteoclastic bone resorption, which could not be reproduced by combining the parent compound with nitric oxide (NO) donors. The aim of this study was to investigate the mechanism by which HCT1026 inhibits bone resorption. We compared the effects of flurbiprofen and HCT1026 on osteoclast and osteoblast activity with those of HCT1027--an analogue of HCT1026, which lacks an NO-donating moiety. We found that HCT1026 and HCT1027 inhibited bone resorption in interleukin (IL)-1-stimulated murine osteoblast-bone marrow cocultures, with half-maximal effects (IC50) at 20 +/- 5 microM for HCT1026 and 25 +/- 6 microM for HCT1027 compared with 399 +/- 25 microM for flurbiprofen (P < 0.0001). These differences were unrelated to cyclooxygenase (COX) inhibition since HCT1026 and HCT1027 were about seven to eight times less potent than flurbiprofen at inhibiting COX-1 activity and half as potent at inhibiting COX-2 activity. Further studies showed that HCT1026 and HCT1027 activated caspase-3 in rabbit osteoclasts and promoted osteoclast apoptosis, a...Continue Reading

References

Apr 1, 1996·Bone·S J WimalawansaC Yallampalli
Jun 28, 2000·Proceedings of the National Academy of Sciences of the United States of America·R J van't HofS H Ralston
Jul 17, 2001·Immunology·R J van't Hof, S H Ralston
Feb 18, 2003·Fundamental & Clinical Pharmacology·John L Wallace, Piero Del Soldato

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Citations

May 8, 2007·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Francesco CilurzoLuisa Montanari
Mar 15, 2015·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Modesto de CandiaCosimo D Altomare
Apr 19, 2013·The Journal of Pharmacology and Experimental Therapeutics·Mirco GovoniJon O Lundberg
Nov 3, 2017·Medicinal Research Reviews·Catarina OliveiraFernanda Borges

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