scholarly journals Activation of gelatinase–tissue-inhibitors-of-metalloproteinase complexes by matrilysin

1998 ◽  
Vol 331 (3) ◽  
pp. 965-972 ◽  
Author(s):  
Dorothea C. von BREDOW ◽  
Anne E. CRESS ◽  
Eric W. HOWARD ◽  
Timothy G. BOWDEN ◽  
Raymond B. NAGLE
Keyword(s):  
Inflammatory Cells ◽  
Prostate Tissue ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Gelatinase A ◽  
Tissue Inhibitors ◽  
Gelatinase B ◽  
Tissue Inhibitors Of Metalloproteinase ◽  
Proteolytic Cascade ◽  
Human Prostate Tissue

Matrilysin, gelatinase A and gelatinase B are matrix metalloproteinases (MMPs) implicated in normal and pathological processes that require remodelling of the extracellular matrix. In human prostate tissue, matrilysin is synthesized in ducts surrounded by inflammatory cells, and focally in prostate carcinoma, but not in normal glands. Gelatinase B expression is restricted to inflammatory cells. Gelatinase A can be found in both benign and malignant prostate tissue. MMP activities are regulated by their transition from latent to activated forms, as well as by the presence of tissue inhibitors of metalloproteinases (TIMPs). We investigated whether matrilysin can activate progelatinases A and B in the presence of their bound inhibitors TIMP2 and TIMP1 respectively. Incubation of progelatinase B–TIMP1 complex with active matrilysin resulted in 78 and 68 kDa active forms, as measured by SDS–PAGE and enzyme activity assays. TIMP-free gelatinase B was also activated by matrilysin. In addition, activation of progelatinase B by matrilysin was demonstrated in the conditioned medium of phorbol ester-treated HT1080 cells, confirming the results obtained in the in vitro experiments. In contrast, matrilysin did not proteolytically cleave gelatinase A–TIMP2 complex, but led to a transient increase in gelatinolytic activity of the proenzyme. Matrilysin did not enhance the autocatalytic conversion of its own proform. The data presented here suggest that matrilysin participates in a proteolytic cascade and can activate gelatinases in the presence of TIMPs.

Matrix metalloproteinases and tissue inhibitors of metalloproteinases in human gliomas

1995 ◽  
Vol 83 (2) ◽  
pp. 298-307 ◽  
Author(s):  
Atsuhisa Nakano ◽  
Eiichi Tani ◽  
Kaoru Miyazaki ◽  
Yoshihiro Yamamoto ◽  
Jun-ichi Furuyama
Keyword(s):  
Cell Lines ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Gelatinase A ◽  
Human Gliomas ◽  
Glioma Invasion ◽  
Gelatinase B ◽  
Mmp Genes ◽  
Interstitial Collagenase

✓ The gene expression of five matrix metalloproteinases (MMPs) and two tissue inhibitors of metalloproteinases (TIMPs) was studied in human gliomas in vivo and in vitro to evaluate their roles in glioma invasion. Simultaneous expression of one to four MMP genes and two TIMP genes was found in 17 surgical glioma specimens, and one MMP (gelatinase A) gene and two TIMP genes were simultaneously expressed in tissue of three brains. The concomitant overexpression of gelatinase A, gelatinase B, and occasional matrilysin genes was associated with the malignancy of gliomas and accompanied by overexpression of the TIMP-1 gene. In five human glioma cell lines, gelatinase A, TIMP-1, and TIMP-2 genes were constitutively expressed in all cell lines: the matrilysin gene in three cell lines; the stromelysin gene in two cell lines; and the interstitial collagenase gene in one cell line. There was a clear difference in the expression of gelatinase B and stromelysin genes between surgical glioma specimens and glioma cell lines: the gelatinase B gene was not expressed constitutively in vitro but was overexpressed in vivo, whereas the stromelysin gene was not expressed in vivo but was expressed in some cell lines. To find the cause of that difference in vivo and in vitro, the transcriptional regulations of MMP and TIMP genes by tumor promoter, growth factors, or cytokines were studied in vitro. Interstitial collagenase, gelatinase B, stromelysin, and TIMP-1 genes were upregulated in many cell lines by phorbol-12-myristate-13-acetate (PMA) and in some cell lines by epidermal growth factor, tumor necrosis factor-α, or interleukin-1β. Transforming growth factor-β1 (TGFβ1) upregulated gelatinase A and matrilysin genes in some cell lines, and there were no clear responses from any MMP and TIMP genes to interleukin-6. Thus, the transcriptional modulation of MMP genes by these growth factors and cytokines seemed insufficient to explain the difference in gelatinase B and stromelysin gene expressionsin vivo and in vitro and was suggestive of the genetic alteration of glioma cells in vitro, the heterogeneous cell population in glioma tissues, or both. Furthermore, the in vitro invasion of glioma cells through Matrigel in response to PMA, TGFβ1, or TIMP-1 was assessed by chemoinvasion assay. In most cell lines, invasion was significantly stimulated by PMA or TGFβ1 but suppressed by TIMP-1. These in vivo and in vitro studies are strongly suggestive of the important roles of some MMPs, especially gelatinase A, gelatinase B, and matrilysin, in the glioma invasion.

Expression of Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases in Human Pancreatic Adenocarcinomas: Clinicopathologic and Prognostic Significance of Matrilysin Expression

2001 ◽  
Vol 19 (4) ◽  
pp. 1118-1127 ◽  
Author(s):  
Hiroyuki Yamamoto ◽  
Fumio Itoh ◽  
Shouhei Iku ◽  
Yasushi Adachi ◽  
Hiroshi Fukushima ◽  
...  
Keyword(s):  
Overall Survival ◽  
Matrix Metalloproteinases ◽  
Pancreatic Carcinoma ◽  
Prognostic Significance ◽  
Carcinoma Cells ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Invasive Front ◽  
Clinicopathologic Characteristics ◽  
Tissue Inhibitors

PURPOSE: A disruption in the balance between the matrix metalloproteinases (MMPs) and their natural inhibitors, tissue inhibitors of metalloproteinases (TIMPs), has been implicated in the progression of many types of cancer. The aim of this study was to determine whether a specific MMP or TIMP has clinicopathologic and prognostic significance in pancreatic carcinoma. PATIENTS AND METHODS: Using immunohistochemistry, we analyzed 70 pancreatic ductal adenocarcinoma tissues for expression of MMP-1, MMP-2, MMP-3, MMP-7 (matrilysin), MMP-9, MT1-MMP, TIMP-1, and TIMP-2. The results were matched with clinicopathologic characteristics and patients’ survival. The effects of the suppression of a specific MMP on in vitro invasiveness of pancreatic carcinoma cells were also examined. RESULTS: Expression of MMP-1, MMP-2, MMP-3, matrilysin, MMP-9, MT1-MMP, TIMP-1, and TIMP-2 was detected in either tumor cells or tumor stromal cells, or in both components, at varying frequencies. Among MMPs, matrilysin showed a unique distribution in the tumor nests; its expression was usually most pronounced at the invasive front of the tumors. Sections with immunostaining signals in more than 30% of carcinoma cells at the invasive front, which were observed in 40 cases (57%), were judged to be positive for matrilysin. Matrilysin positivity was significantly correlated with pT, pN, and pM categories and with more advanced pathologic tumor-node-metastasis stages. Patients with matrilysin-positive carcinoma had a significantly shorter overall survival time than did those with matrilysin-negative carcinoma. Matrilysin was a significant independent prognostic factor for overall survival in multivariate analysis. In contrast, there was no correlation between the presence of other MMPs or TIMPs and clinicopathologic characteristics, nor was the presence of individual MMPs or TIMPs related to survival. Antisense matrilysin-transfected CFPAC-1 cells expressed reduced levels of matrilysin and demonstrated a similar growth potential but were less invasive in vitro compared with neotransfected CFPAC-1 cells. CONCLUSION: Our results suggest that matrilysin may play a key role in progression of pancreatic carcinoma and thereby contribute to a poor prognosis. Because different synthetic MMP inhibitors affect different types of MMPs to a different degree, examination of the expression of MMPs, especially that of matrilysin, may serve as an indicator for selecting the most effective MMP inhibitor.

Production of tissue inhibitors of metalloproteinases (TIMPs) by pig ovarian cells in vivo and the effect of TIMP-1 on steroidogenesis in vitro

Reproduction ◽  
2000 ◽  
pp. 73-81 ◽  
Author(s):  
EM Shores ◽  
MG Hunter
Keyword(s):  
Follicular Fluid ◽  
Theca Cell ◽  
Tissue Type ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Free System ◽  
Tissue Inhibitors ◽  
Theca Cells ◽  
Ovarian Cells ◽  
Follicle Size

Precisely which ovarian cells produce tissue inhibitors of metalloproteinases (TIMPs) is unclear. Although granulosa cells are reported to produce TIMPs, thecal TIMP production has not been investigated nor has the influence of TIMPs on theca cells. Furthermore, although periovulatory follicles have been examined, little is known about smaller ovarian follicles. Follicles >/= 2 mm in diameter were collected from Large White hybrid gilts on the day before predicted oestrus (n = 3) or after hCG treatment (n = 3) and divided into 1 mm size classes. Small (2 to < 5 mm) follicles were kept intact, whereas follicles >/= 5 mm were separated into follicular fluid, granulosa and theca cell compartments. After homogenization, TIMP-1, -2 and -3 were detected by reverse zymography. Theca cells (50 x 10(3) per well) were cultured with TIMP-1 (10, 100 or 200 ng ml(-1) with or without long-R3 insulin-like growth factor I (IGF-I)) in a serum-free system to investigate the effect on steroidogenesis and the number of cells. Both large and small pig follicles produced TIMPs and TIMP-1, -2 and -3 were detected in follicular fluid, granulosa and theca cell samples. There was a phase x tissue type interaction for the presence of both TIMP-1 and -2 (P < 0.03, P < 0.05, respectively), and TIMPs were detected in more granulosa and theca cell samples after hCG than during the follicular phase. The concentrations were influenced by the type of tissue (TIMP-1, P < 0.005; TIMP-2, P < 0.005, TIMP-3, P > 0.05), and the highest concentrations occurred in the theca tissue. There were tissue type x follicle size interactions for the presence of both TIMP-1 and -2 (P < 0.001). In vitro, TIMP-1 increased thecal steroidogenesis after 144 h (oestradiol, P < 0.05, progesterone, P < 0.001) but reduced the number of viable cells (P < 0.001). In conclusion, TIMP-1, -2 and -3 were present in large and small pig follicles and were produced by both granulosa and theca cells, although concentrations differed with the type of tissue. Production was regulated by factors including follicle size and phase of the oestrous cycle. In addition to controlling tissue remodelling, TIMP-1 may also regulate steroidogenesis.

scholarly journals TIMP-3 inhibits the procollagen N-proteinase ADAMTS-2

2006 ◽  
Vol 398 (3) ◽  
pp. 515-519 ◽  
Author(s):  
Wei-Man Wang ◽  
Gaoxiang Ge ◽  
N. H. Lim ◽  
Hideaki Nagase ◽  
Daniel S. Greenspan
Keyword(s):  
Extracellular Matrix ◽  
Matrix Metalloproteinases ◽  
Bone Morphogenetic Protein ◽  
Inhibitory Activity ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Tissue Inhibitors ◽  
Morphogenetic Protein ◽  
Ecm Extracellular Matrix ◽  
Bone Morphogenetic Protein 1

ADAMTS-2 is an extracellular metalloproteinase responsible for cleaving the N-propeptides of procollagens I–III; an activity necessary for the formation of collagenous ECM (extracellular matrix). The four TIMPs (tissue inhibitors of metalloproteinases) regulate the activities of matrix metalloproteinases, which are involved in degrading ECM components. Here we delineate the abilities of the TIMPs to affect biosynthetic processing of procollagens. TIMP-1, -2 and -4 show no inhibitory activity towards ADAMTS-2, in addition none of the TIMPs showed inhibitory activity towards bone morphogenetic protein 1, which is responsible for cleaving procollagen C-propeptides. In contrast, TIMP-3 is demonstrated to inhibit ADAMTS-2 in vitro with apparent Ki values of 160 and 602 nM, in the presence of heparin or without respectively; and TIMP-3 is shown to inhibit procollagen processing by cells.

Sign in / Sign up

Export Citation Format

Share Document