Overexpression of matrix metalloproteinase (MMP)-9 correlates with metastatic potency of spontaneous and 4-hydroxyaminoquinoline 1-oxide (4-HAQO)-induced transplantable osteosarcomas in rats

In the present experiment, the expression of matrix metalloproteinase (MMP) -2 and MMP-9, key proteins in the MMP family, and the tissue inhibitors of metalloproteinase (TIMP)-1 and TIMP-2, antagonistic proteins against MMP-2 and MMP-9, respectively, were investigated by Northern blot analysis in rat transplantable osteosarcomas with high and low metastatic potencies. Two t ransplantable osteosarcomas, one induced with the carcinogen, 4-hydroxyamin oquinoline 1-oxide (4-HAQO) (COS, chemical carcinogen-induced osteosarcoma) , and the other, a spontaneous lesion (SOS, spontaneous osteosarcoma), were repeatedly transplanted from lung nodules to generate lines with high meta static potency, C-SLM (chemical carcinogen-induced osteosarcoma, selected l ung metastatic lesions) and S-SLM (spontaneous osteosarcoma, selected lung metastatic lesions), respectively. MMP-9 was overexpressed in both S-SLM an d C-SLM, and TIMP-2 in the case of S-SLM. Neither MMP-2 nor TIMP-1 was over expressed in either of the transplantable osteosarcomas with high metastati c potentials. The active form MMP-9, studied by zymography, increased in S- SLM and C-SLM but not in SOS and COS. MMP-9 mRNA expression was highly corr elated with the gelatinolytic activity of active form MMP-9 (r = 0.85, P < 0.0001) and with the activation ratio of MMP-9 (r = 0.83, P < 0.0001). Howe ver, the active form MMP-2 was not detectable in all cases. These results s uggest that overexpression of MMP-9 mRNA is one of the essential factors in the acquisition of metastatic potential in rat transplantable osteosarcoma s. (C) 1999 Published by Elsevier Science Ltd. All rights reserved.