Three different membrane-type matrix metalloproteinases (MT1-, MT2-, and MT3-MMPs) are known to activate in vitro the zymogen of MMP-2 (pro-MMP-2, progelatinase A), which is one of the key MMPs in invasion and metastasis of various cancers. In the present study, we have examined production and activation of pro-MMP-2, expression of MT1-, MT2-, and MT3-MMPs and their correlation with pro-MMP-2 activation, and localization of MMP-2, MT1-MMP, and MT2-MMP in human astrocytic tumors. The sandwich enzyme immunoassay demonstrates that the production levels of pro-MMP-2 in the anaplastic astrocytomas and glioblastomas are significantly higher than that in the low-grade astrocytomas (P<0.05 and P<0.01, respectively), metastatic brain tumors (P<0.05), or normal brains (P<0.01). Gelatin zymography indicates that the pro-MMP-2 activation ratio is significantly higher in the glioblastomas than in other astrocytic tumors (P<0.01), metastatic brain tumors (P<0.01), and normal brains (P<0.01). The quantitative reverse transcription polymerase chain reaction analyses demonstrate that MT1-MMP and MT2-MMP are expressed predominantly in glioblastoma tissues (17/17 and 12/17 cases, respectively), and their expression levels increase significantly as tumor grade increases. MT3-MMP is detectable in both astrocytic tumor and normal brain tissues, but the mean expression level is approximately 50-fold lower compared with that of MT1-MMP and MT2-MMP in the glioblastomas. The activation ratio of pro-MMP-2 correlates directly with the expression levels of MT1-MMP and MT2-MMP but not MT3-MMP. In situ hybridization indicates that neoplastic astrocytes express MT1-MMP and MT2-MMP in the glioblastoma tissues (5/5 cases and 5/5 cases, respectively). Immunohistochemically, MT1-MMP and MT2-MMP are localized to the neoplastic astrocytes in glioblastoma samples (17/17 cases and 12/17 cases, respectively), which are also positive for MMP-2. In situ zymography shows gelatinolytic activity in the glioblastoma tissues but not in the normal brain tissues. These results suggest that both MT1-MMP and MT2-MMP play a key role in the activation of pro-MMP-2 in the human malignant astrocytic tumors and that the gelatinolytic activity is involved in the astrocytic tumor invasion.

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We examined production and tissue localization of matrix metalloproteinase (MMP)‐1 (tissue collagenase), MMP‐2 (gelatinase A), MMP‐3 (stromelysin‐1), MMP‐9 (gelatinase B), tissue inhibitors of metalloproteinase (TIMP)‐1 and TIMP‐2 in human breast carcinomas. In more than half of the cases, MMP‐1, MMP‐2, MMP‐9, TIMP‐1 and TIMP‐2 were immunolocalized in carcinoma cells and MMP‐2 was on the carcinoma cell membranes as well, whereas MMP‐3 was positively stained in less than 15% of the cases. MMP‐1 staining in carcinoma cells was significantly higher in scirrhous carcinoma than in other types of carcinoma. MMP‐9 expression was remarkably higher in the carcinoma cases with lymphnode metastasis than in the non‐metastatic cases. MMP‐3 was mainly expressed in T‐lymphocytes infiltrated in the tumor stroma. Stromal fibroblasts were positive for all these MMPs except for MMP‐3. The TIMP‐1 levels released into the culture media by carcinoma tissues were significantly lower than those by fibroadenoma tissues, although there were no significant differences in the levels of MMP‐1, MMP‐2, MMP‐9 and TIMP‐2. Gelatin zymographical analyses showed that the activation rate of the zymogen of MMP‐2 (proMMP‐2) is significantly higher in the more advanced carcinoma group with lymphnode metastasis than in the metastasis‐negative and fibroadenoma groups. These data indicate that MMP‐1, MMP‐2 and MMP‐9 are highly expressed in human breast carcinoma tissue and suggest that activation of proMMP‐2 may be an indicator of lymphnode metastasis of the breast carcinoma.

Objective. To evaluate the efficacy of stromelysin-1 (matrix metalloproteinase-3 [MMP3]) and tissue inhibitor of metalloproteinases-1 (TIMP-1) in serum as markers for joint inflammation in rheumatoid arthritis (RA).Methods. Levels of both macromolecules in sera from 97 healthy controls, 109 patients with RA, and 47 patients with osteoarthritis (OA) were measured by respective 1-step sandwich enzyme immunoassays. In the patients with RA, serum levels of MMP-3 and TIMP-1 were investigated in relation to laboratory and clinical measures of disease activity. In addition, the relationships between serum and synovial fluid (SF) levels in paired samples from individual patients were examined.Results. Serum levels of both MMP-3 and TIMP-1 in RA patients were significantly higher than those in OA patients and in healthy controls (P < 0.001), and were shown to correlate with traditional systemic markers of inflammation including the erythrocyte sedimentation rate and C-reactive protein level, and with the Lansbury articular index. In addition, it was noted that serum levels of MMP-3 correlated with the corresponding values in paired SF samples obtained concurrently from patients with RA (r, = 0.588, P <