Influence of cytokine inhibitors on concentration and activity of MMP-1 and MMP-3 in disc herniation.
BACKGROUND
Spontaneous resorption of disc herniation (DH) after sciatica is well documented. The matrix metalloproteinases (MMP)-1 and MMP-3 are enzymes potentially involved in this process. Glucocorticoid injections are commonly used for treatment, and other anti-inflammatory molecules like tumor necrosis factor (TNF) inhibitors are under clinical investigation. However, little is known about the effect of these molecules on DH resorption.


METHODS
DH tissue was harvested from patients undergoing surgery for sciatica. Samples were thoroughly washed. Diced explants were cultured ex-vivo in 1) 0.5 ml Dulbecco's modified Eagle's medium (DMEM) 10% fetal calf serum (FCS), (controls), 2) recombinant interleukin 1 receptor antagonist (IL-1Ra), (100 ng/ml), 3) dexamethasone (10E-5 M), or 4) TNF inhibitor monoclonal antibody (10 microg/ml). Supernatants were harvested at 48 hours and frozen. Immunocapture activity assays determined total MMP activity, active MMP levels and pro-MMP levels.


RESULTS
Fourteen DH tissue samples were analysed. Levels of all forms of MMP-3 were higher than the respective levels of MMP-1(P < 0.01). In particular, the median (interquartile range [IQR]) total MMP-3 level was 0.97 (0.47 - 2.19) ng/mg of tissue compared to 0.024 (0.01 - 0.07) ng/mg of total MMP-1 level (P < 0.01). Incubation with IL-1Ra, dexamethasone, or TNF inhibitors significantly decreased levels of all forms of MMP-3 (P < 0.05). Dexamethasone significantly decreased the ratio of active MMP-3 to total MMP-3 activity. A significant inhibitory effect of dexamethasone was observed only on active MMP-1, while IL-1 and TNF inhibitor had no significant effect on any form.


CONCLUSIONS
MMP-3 appears to play a greater role than MMP-1 in DH resorption. Dexamethasone, IL-1-Ra and TNF inhibitor decreased active MMP-3, indicating that the clinical use of these drugs may affect the resorption of DH under certain conditions.
Genevay
Stéphane
S
Division of Rheumatology, University Hospitals of Geneva, Avenue Beau-Séjour 26, 1211 Geneva 14, Switzerland. stephane.genevay@hcuge.ch
Finckh
Axel
A
Mezin
Françoise
F
Tessitore
Enrico
E
Guerne
Pierre-André
PA
D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology; D007405:Intervertebral Disc Displacement / Q000150:complications / Q000201:enzymology* / Q000276:immunology; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000187:drug effects / Q000378:metabolism*; D019278:Matrix Metalloproteinase 3 / Q000187:drug effects / Q000378:metabolism*; D008875:Middle Aged; D012585:Sciatica / Q000209:etiology / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D053590:Interleukin 1 Receptor Antagonist Protein; D014409:Tumor Necrosis Factor-alpha; D003907:Dexamethasone; D019278:Matrix Metalloproteinase 3; D020781:Matrix Metalloproteinase 1