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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.
Ann Rheum Dis. 2005 Jun; 64(6):891-8.AR

Abstract

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 1beta (IL1beta) and treated with or without: licofelone (0.3, 1, or 3 mug/ml); NS-398 (10 muM; a specific COX-2 inhibitor); or BayX-1005 (10 muM; 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 IL1beta induced MMP-13 signalling pathways was determined using specific ELISA for phosphorylated MAP kinases and transcription factors.

RESULTS

Licofelone dose dependently inhibited the IL1beta 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.

Authors+Show Affiliations

Osteoarthritis Research Unit, University of Montreal Hospital Centre, Notre-Dame Hospital, 1560 Sherbrooke St East, Montreal, Quebec, Canada H2L 4M1.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15498796

Citation

Boileau, C, et al. "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." Annals of the Rheumatic Diseases, vol. 64, no. 6, 2005, pp. 891-8.
Boileau C, Pelletier JP, Tardif G, et al. 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. Ann Rheum Dis. 2005;64(6):891-8.
Boileau, C., Pelletier, J. P., Tardif, G., Fahmi, H., Laufer, S., Lavigne, M., & Martel-Pelletier, J. (2005). 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. Annals of the Rheumatic Diseases, 64(6), 891-8.
Boileau C, et al. 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. Ann Rheum Dis. 2005;64(6):891-8. PubMed PMID: 15498796.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Boileau,C, AU - Pelletier,J-P, AU - Tardif,G, AU - Fahmi,H, AU - Laufer,S, AU - Lavigne,M, AU - Martel-Pelletier,J, Y1 - 2004/10/21/ PY - 2004/10/23/pubmed PY - 2005/7/12/medline PY - 2004/10/23/entrez SP - 891 EP - 8 JF - Annals of the rheumatic diseases JO - Ann. Rheum. Dis. VL - 64 IS - 6 N2 - 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 1beta (IL1beta) and treated with or without: licofelone (0.3, 1, or 3 mug/ml); NS-398 (10 muM; a specific COX-2 inhibitor); or BayX-1005 (10 muM; 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 IL1beta induced MMP-13 signalling pathways was determined using specific ELISA for phosphorylated MAP kinases and transcription factors. RESULTS: Licofelone dose dependently inhibited the IL1beta 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. SN - 0003-4967 UR - https://www.unboundmedicine.com/medline/citation/15498796/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_ L2 - https://ard.bmj.com/cgi/pmidlookup?view=long&pmid=15498796 DB - PRIME DP - Unbound Medicine ER -