Article Text

Download PDFPDF
The regulation of human MMP-13 by licofelone, an inhibitor of cyclo-oxygenases and 5-lipoxygenase, in human osteoarthritic chondrocytes is mediated by the inhibition of the p38 MAP kinase signalling pathway
  1. C Boileau1,
  2. J-P Pelletier1,
  3. G Tardif1,
  4. H Fahmi1,
  5. S Laufer2,
  6. M Lavigne3,
  7. J Martel-Pelletier1
  1. 1Osteoarthritis Research Unit, Notre-Dame Hospital, University of Montreal Hospital Centre, Montreal, Quebec, Canada
  2. 2Eberhard-Karls University Tübingen, Tübingen, Germany
  3. 3Maisonneuve-Rosemont Hospital, Montreal
  1. Correspondence to:
    Professor Johanne Martel-Pelletier
    Osteoarthritis Research Unit, University of Montreal Hospital Centre, Notre-Dame Hospital, 1560 Sherbrooke St East, Montreal, Quebec, Canada H2L 4M1;


Background: MMP-13 is one of the most important metalloproteases (MMP) involved in osteoarthritis. Licofelone, a novel dual inhibitor of cyclo-oxygenases (COX) and 5-lipoxygenase (5-LOX), can modulate MMP-13 production in human osteoarthritis chondrocytes.

Objective: To evaluate the impact of licofelone on MMP-13 expression/production, promoter, and major MAP kinase signalling pathways and transcription factors.

Methods: Human osteoarthritis chondrocytes were stimulated by interleukin 1β (IL1β) and treated with or without: licofelone (0.3, 1, or 3 μg/ml); NS-398 (10 μM; a specific COX-2 inhibitor); or BayX-1005 (10 μM; a specific 5-LOX inhibitor). MMP-13 synthesis was determined by specific enzyme linked immunosorbent assay, and expression by real time polymerase chain reaction. The effect of licofelone on the MMP-13 promoter was studied through transient transfection; dexamethasone (10−7 M) was used as comparison. The effect on IL1β induced MMP-13 signalling pathways was determined using specific ELISA for phosphorylated MAP kinases and transcription factors.

Results: Licofelone dose dependently inhibited the IL1β stimulated production and expression of MMP-13. NS-398 and BayX-1005 had very little effect. Licofelone also inhibited MMP-13 transcription on each of the promoter constructs used. The licofelone inhibition was comparable to that obtained with dexamethasone. Licofelone had no effect on phosphorylated p44/42 or JNK1/2; however, it decreased phosphorylated c-jun and inhibited phosphorylated p38, CREB, and AP-1 activity.

Conclusions: Licofelone inhibited MMP-13 production under proinflammatory conditions on human osteoarthritis chondrocytes, through inhibition of the p38/AP-1 pathway and the transcription factor CREB. This may explain some of the mechanisms whereby licofelone exerts its positive effect on osteoarthritic changes.

  • COX, cyclo-oxygenase
  • EMSA, electrophoretic mobility shift assay
  • LOX, lipoxygenase
  • MMP, matrix metalloproteases
  • PMA, phorbol-12-myristate-13-acetate
  • MMP-13
  • cartilage
  • licofelone
  • osteoarthritis

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.