Induction of matrix metalloproteinase activation cascades based on membrane-type 1 matrix metalloproteinase: associated activation of gelatinase A, gelatinase B and collagenase 3

Abstract

SW1353 chondrosarcoma cells cultured in the presence of interleukin-1, concanavalin A or PMA secreted procollagenase 3 (matrix metalloproteinase-13). The enzyme was detected in the culture medium by Western blotting using a specific polyclonal antibody raised against recombinant human procollagenase 3. Oncostatin M enhanced the interleukin-1-induced production of procollagenase 3, whereas interleukin-4 decreased procollagenase 3 synthesis. The enzyme was latent except when the cells had been treated with concanavalin A, when a processed form of 48 kDa, which corresponds to the active form, was found in the culture medium and collagenolytic activity was detected by degradation of 14C-labelled type I collagen. The concanavalin A-induced activation of procollagenase 3 coincided with the processing of progelatinase A (matrix metalloproteinase-2) by the cells, as measured by gelatin zymography. In addition, progelatinase B (matrix metalloproteinase-9) was activated when gelatinase A and collagenase 3 were in their active forms. Concanavalin A treatment of SW1353 cells increased the amount of membrane-type-1 matrix metalloproteinase protein in the cell membranes, suggesting that this membrane-bound enzyme participates in an activation cascade involving collagenase 3 and the gelatinases. This cascade was effectively inhibited by tissue inhibitors of metalloproteinases-2 and -3. Tissue inhibitor of metalloproteinases-1, which is a much weaker inhibitor of membrane-type 1 matrix metalloproteinase than tissue inhibitors of metalloproteinases-2 and -3 [Will, Atkinson, Butler, Smith and Murphy (1996) J. Biol. Chem. 271, 17119-17123], was a weaker inhibitor of the activation cascade.

Type IV Collagen Induces Matrix Metalloproteinase 2 Activation in HT1080 Fibrosarcoma Cells

“…6A and 6B, lanes 2-4). The occurrence of this latter form has been associated with the ability of the cells to activate MMP-2 and to degrade gelatin [13,29,59]. Consistent with these data, our results also demonstrated an obvious association between the TPA-and ConA-induced pro-MMP-2 activation and MT1-MMP processing into a 43-kDa form.…”

“…On the basis of the dual role of TIMP-2 during MMP-2 activation, promoting MMP-2 activation when present at low concentrations [20,29,31,54,63,64], but acting as an efficient inhibitor of this process when present at higher doses [19,20,26,31,53,[65][66][67], we hypothesized that modulations of TIMP-2 concentration could play important roles in the regulation of MMP-2 processing. Consequently, we investigated the modifications of both TIMP-2 concentration and distribution between conditioned media and cell extracts induced by MMP-2-activating treatments.…”

“…Sato and co-workers have identified MT1-MMP (membrane type 1 MMP or MMP-14): a MMP possessing a hydrophobic C-terminal transmembrane domain, which is considered as a physiological MMP-2 activator [22][23][24][25]. The active form of MT1-MMP, which is generated through a furin-dependent mechanism [26,27], binds TIMP-2 through the interaction of the N-terminal domains of each protein, thereby docking soluble TIMP-2 to the cell surface [20,[28][29][30]. This bimolecular complex subsequently functions as a receptor for the secreted pro-MMP-2, through interactions of their C-terminal domains, thus forming a MT1-MMP/TIMP-2/MMP-2 ternary complex.…”

Assessment of the gene expression profile of differentiated and dedifferentiated human fetal chondrocytes by microarray analysis

“…Concordant with these results, we also observed TWIST transcripts in HFCs that were transformed with a retroviral vector expressing the E6 and E7 proteins from the human papilloma virus and grown for multiple passages in the dedifferentiated monolayer state and in HFCs passaged 4 times at 11-day intervals in monolayer ( Figure 5B). In contrast, we did not detect TWIST expression in HTB-94 human chondrosarcoma cells, which appear to maintain a more differentiated state (47).…”

“…61). HIF-1␣ is an HLH-PAS (Per, ARNT, Sim) domain-containing transcription factor that, along with HIF-1␤ (also known as ARNT, and also an HLH-PAS factor), forms the heterodimeric factor HIF-1 in response to hypoxia (47,62). When cells are subjected to hypoxic conditions or agents such as Ni, Co, Mn, CO, and/or antioxidants, the HIF-1␣ protein becomes induced and can heterodimerize with HIF-1␤, leading to the activation by HIF-1 of downstream genes involved in the response to hypoxia, such as those mediating anaerobic metabolism, oxygen transport, vasodilation, and blood vessel formation (61).…”