Endothelin-1 (ET-1) promotes MMP-2 and MMP-9 induction involving the transcription factor NF-κB in human osteosarcoma

In the present study, we have investigated the effect of (i) ET-I (endothelin-1) and its precursor, big ET-1, on MMP (matrix metal loproteinase)-2 and MMP-9 synthesis and activity in osteosarcoma tissue, and (ii) ET-I receptor antagonists on cell invasion. Using Western blotting, zymography, RT-PCR (reverse transcription-PCR), immunohistochemistry, immunofluorescence and Northern blotting, we have shown that ET-I and ET-I receptors (ETA and ETB) were expressed in these cells. Additionally, we have demonstrated that ET-I markedly induced the synthesis and activity of MMP-2, which was significantly increased when compared with MMP-9. Furthermore, inhibition of NF-kappa B (nuclear factor kappa B) activation blocked MMP-2 production and activity, indicating the involvement of NF-kappa B, a ubiquitous transcription factor playing a central role in the differentiation, proliferation and malignant transformation. Since ET-I acts as an autocrine mediator through gelatinase induction and because inhibition of ETA receptor is beneficial for reducing both basal and ET-I-induced osteosarcoma cell invasion, targeting this receptor could be an attractive therapeutic alternative for the successful treatment of osteosarcoma.