Licofelone (ML-3000), a dual inhibitor of 5-lipoxygenase and cyclooxygenase, reduces the level of cartilage chondrocyte death in vivo in experimental dog osteoarthritis: inhibition of pro-apoptotic factors

Abstract : OBJECTIVE: 2002To evaluate in vivo therapeutic efficacy of licofelone, a novel competitive dual inhibitor of 5-lipoxygenase (5-LOX) and cyclooxygenase (COX) in chondrocyte death in the canine ligament transection model of osteoarthritis (OA), and to explore its effect on factors involved in the apoptotic phenomenon, i.e., caspase-3, COX-2, and inducible nitric oxide synthase (iNOS). METHODS: Cartilage specimens were obtained from 3 experimental groups of dogs: Group 1, dogs subjected to sectioning of the anterior cruciate ligament of the right knee and given placebo treatment; Groups 2 and 3, operated dogs that received oral treatment with licofelone (2.5 or 5.0 mg/kg/day, respectively) for 8 weeks starting immediately after surgery. All dogs were killed 8 weeks postsurgery. The cartilage level of chondrocyte death was detected by TUNEL reaction. Cartilage distribution of caspase-3, COX-2, and iNOS was documented by immunohistochemistry using specific antibodies, and other levels were quantified by morphometric analysis. RESULTS: In cartilage specimens from placebo treated dogs a large number of chondrocytes in the superficial layers stained positive for TUNEL reaction. Treatment with therapeutic concentrations of licofelone (2.5 and 5.0 mg/kg/day) markedly reduced the level of chondrocyte apoptosis to the same extent in both therapeutic groups (p < 0.0001, p < 0.002, respectively). In these groups, the levels of caspase-3, COX-2, and iNOS in cartilage from both condyles and plateaus were also significantly decreased (p < 0.0001, p < 0.0001, p < 0.0002, respectively) compared to the control (placebo) group. CONCLUSION: Licofelone is an effective treatment in vivo, capable of reducing the level of OA chondrocyte death. This effect is likely mediated by a decrease in the level of caspase-3 activity, which may be related to the reduced production of 2 major factors involved in chondrocyte apoptosis, NO and prostaglandin E2. These findings may explain some of the mechanisms by which licofelone reduces the progression of experimental OA.
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Contributor : Jean-Yves Jouzeau <>
Submitted on : Wednesday, April 25, 2018 - 3:12:20 PM
Last modification on : Friday, September 20, 2019 - 2:00:03 PM

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  • HAL Id : hal-01778282, version 1
  • PUBMED : 12136904

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Christelle Boileau, Johanne Pelletier, Jean-Yves Jouzeau, Patrick Netter, Florina Moldovan, et al.. Licofelone (ML-3000), a dual inhibitor of 5-lipoxygenase and cyclooxygenase, reduces the level of cartilage chondrocyte death in vivo in experimental dog osteoarthritis: inhibition of pro-apoptotic factors. Journal of Rheumatology, Journal of Rheumatology Publishing Company Limited, 2002, 29 (7), pp.1446-53. ⟨hal-01778282⟩

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