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.
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 humanosteoarthritis chondrocytes. OBJECTIVE: To evaluate the impact of licofelone on MMP-13 expression/production, promoter, and major MAP kinase signalling pathways and transcription factors. METHODS:Humanosteoarthritis 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 humanosteoarthritis 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: R Altman; E Asch; D Bloch; G Bole; D Borenstein; K Brandt; W Christy; T D Cooke; R Greenwald; M Hochberg Journal: Arthritis Rheum Date: 1986-08
Authors: M Ståhle-Bäckdahl; B Sandstedt; K Bruce; A Lindahl; M G Jiménez; J A Vega; C López-Otín Journal: Lab Invest Date: 1997-05 Impact factor: 5.662
Authors: J C Fernandes; J Martel-Pelletier; V Lascau-Coman; F Moldovan; D Jovanovic; J P Raynauld; J P Pelletier Journal: J Rheumatol Date: 1998-08 Impact factor: 4.666
Authors: Gaurav Kumar; Jagan Mohan R Patlolla; Venkateshwar Madka; Altaf Mohammed; Qian Li; Yuting Zhang; Laura Biddick; Anil Singh; Allison Gillaspy; Stanley Lightfoot; Vernon E Steele; Levy Kopelovich; Chinthalapally V Rao Journal: Am J Cancer Res Date: 2016-05-01 Impact factor: 6.166
Authors: Isabel García-Arnandis; Maria Isabel Guillén; Francisco Gomar; Jean-Pierre Pelletier; Johanne Martel-Pelletier; Maria José Alcaraz Journal: Arthritis Res Ther Date: 2010-08-27 Impact factor: 5.156