The protective effect of licofelone on experimental osteoarthritis is correlated with the downregulation of gene expression and protein synthesis of several major cartilage catabolic factors: MMP-13, cathepsin K and aggrecanases

Jean-Pierre Pelletier,Pascal Reboul,Christelle Boileau,Johanne Martel-Pelletier,Stefan Laufer,Martin Boily,François Mineau,Julie Brunet,Changshen Geng,Daniel Lajeunesse

doi:10.1186/ar1788

Abstract

This study sought to evaluate the levels of mRNA expression and protein synthesis of MMP-13, cathepsin K, aggrecanase-1 (ADAMTS-4), aggrecanase-2 (ADAMTS-5) and 5-lipoxygenase (5-LOX) in cartilage in the experimental anterior cruciate ligament (ACL) dog model of osteoarthritis (OA), and to examine the effects of treatment with licofelone, a 5-lipoxygenase (LOX)/cyclooxygenase (COX) inhibitor, on the levels of these catabolic factors. Sectioning of the ACL of the right knee was performed in three experimental groups: group 1 received no active treatment (placebo group); and groups 2 and 3 received therapeutic concentrations of licofelone (2.5 or 5.0 mg/kg/day orally, respectively) for 8 weeks, beginning the day following surgery. A fourth group consisted of untreated dogs that were used as normal controls. Specimens of cartilage were selected from lesional areas of OA femoral condyles and tibial plateaus, and were processed for real-time quantitative PCR and immunohistochemical analyses. The levels of MMP-13, cathepsin K, ADAMTS-4, ADAMTS-5 and 5-LOX were found to be significantly increased in OA cartilage. Licofelone treatment decreased the levels of both mRNA expression and protein synthesis of the factors studied. Of note was the marked reduction in the level of 5-LOX gene expression. The effects of the drug were about the same at both tested dosages. In vivo treatment with therapeutic dosages of licofelone has been found to reduce the degradation of OA cartilage in experimental OA. This, coupled with the results of the present study, indicates that the effects of licofelone are mediated by the inhibition of the major cartilage catabolic pathways involved in the destruction of cartilage matrix macromolecules. Moreover, our findings also indicate the possible auto-regulation of 5-LOX gene expression by licofelone in OA cartilage.

Highlights

Along with the graying of the world's population, osteoarthritis (OA), the most common form of arthritis, is becoming an increasingly significant medical and financial burden
This study focuses on the in situ effect of licofelone on the gene expression and protein synthesis of the major collagenolytic enzymes (MMP-13 and cathepsin K) and aggrecandegrading proteases (ADAMTS-4 and ADAMTS-5) in OA cartilage using the experimental anterior cruciate ligament (ACL)
matrix metalloproteinases (MMPs)-13 gene expression and protein synthesis PCR analysis found a marked and significant increase in the expression of mRNA for MMP-13 in OA cartilage compared to normal (Fig. 1)

Summary

Introduction

Along with the graying of the world's population, osteoarthritis (OA), the most common form of arthritis, is becoming an increasingly significant medical and financial burden In this context, the clear need for a better understanding of the disease process has rendered undeniable the importance of finding drugs that can reduce or stop its progression. Leukotriene-B4 (LTB4) has proven to be an important regulating factor in the synthesis of IL-1β by OA synovium [6,7,8] Both in vitro and in vivo studies have demonstrated that the excess production of IL-1β in OA tissue is a key factor in its destruction and in the progression of the disease itself [1,9].

Methods

Results

Conclusion