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.

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.

scholarly journals The Unwounded Skin Remodeling in Animal Models of Diabetes Types 1 and 2

2013 ◽  
pp. 519-526 ◽  
Author(s):  
M. KNAŚ ◽  
M. NICZYPORUK ◽  
A. ZALEWSKA ◽  
H. CAR
Keyword(s):  
Extracellular Matrix ◽  
Matrix Metalloproteinases ◽  
Diabetes Type ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Control Group ◽  
Diabetes Type 1 ◽  
Tissue Inhibitors ◽  
The Matrix

Diabetes mellitus types 1 and 2 are chronic diseases that cause serious health complications, including dermatologic problems. The diabetic skin is characterized by disturbances in collagen metabolism. A tissue remodeling depends on the degradation of extracellular matrix through the matrix metalloproteinases, which are regulated by e.g. the tissue inhibitors of metalloproteinases. The balance between matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) is essential to maintain homeostasis in the skin. The aim of this study was to determine the concentration of metalloproteinase 2, tissue inhibitor of metalloproteinase 3 and the concentration of collagen type 1 in unwounded skin of diabetes type 1 and 2 and healthy controls. The treatment of diabetes resulted in a significant decrease of MMP2, increase of TIMP3 and COL1 concentrations in the skin as compared to the untreated diabetic skin. The concentrations of MMP2 in the skin of treated rats did not show significant differences from the healthy control group. TIMP3 concentrations in the skin of treated rats are not returned to the level observed in the control group. Disturbances of the extracellular matrix of the skin are similar in diabetes type 1 and 2. Application of insulin in diabetes therapy more preferably affects the extracellular matrix homeostasis of the skin.

Dysregulated proteolytic balance as the basis of excess extracellular matrix in fibrotic disease

1997 ◽  
Vol 272 (6) ◽  
pp. R1960-R1965 ◽  
Author(s):  
C. A. Peters ◽  
M. R. Freeman ◽  
C. A. Fernandez ◽  
J. Shepard ◽  
D. G. Wiederschain ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Matrix Metalloproteinases ◽  
Inhibitory Activity ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Fibrotic Disease ◽  
Collagenase Activity ◽  
Tissue Compliance ◽  
Ovine Fetal ◽  
Surgically Induced ◽  
Interstitial Collagenase

To investigate mechanisms of tissue fibrosis, we developed a model of ovine fetal bladder fibrosis due to surgically induced obstruction. Tissues were analyzed for matrix metalloproteinases (MMPs) and their inhibitors, the tissue inhibitors of metalloproteinases (TIMPs). Active MMP-2 was not detected in obstructed bladders, while latent and active forms were detected in normal bladders. MMP-1 (interstitial collagenase) activity was lower in obstructed bladders. MMP inhibitory activity was increased with obstruction, as were levels of TIMP mRNA and protein. These results indicate that the proteins responsible for collagen degradation are present in the developing bladder, and a shift in the proteolytic balance favoring inhibition of degradation occurs in a model of obstruction-induced fibrosis. This altered proteolytic balance favors accumulation of extracellular matrix and decreased tissue compliance characteristic of this and perhaps other fibrotic conditions.

scholarly journals Use of Bmp1/Tll1 Doubly Homozygous Null Mice and Proteomics To Identify and Validate In Vivo Substrates of Bone Morphogenetic Protein 1/Tolloid-Like Metalloproteinases

2003 ◽  
Vol 23 (13) ◽  
pp. 4428-4438 ◽  
Author(s):  
William N. Pappano ◽  
Barry M. Steiglitz ◽  
Ian C. Scott ◽  
Douglas R. Keene ◽  
Daniel S. Greenspan
Keyword(s):  
Bone Morphogenetic Protein ◽  
Residual Activity ◽  
Functional Redundancy ◽  
Bmp Signaling ◽  
Null Mouse ◽  
Genetic Redundancy ◽  
Morphogenetic Protein ◽  
Bone Morphogenetic Protein 1

ABSTRACT Bone morphogenetic protein 1 (BMP-1) and mammalian Tolloid (mTLD), two proteinases encoded by Bmp1, provide procollagen C-proteinase (pCP) activity that converts procollagens I to III into the major fibrous components of mammalian extracellular matrix (ECM). Yet, although Bmp1 −/− mice have aberrant collagen fibrils, they have residual pCP activity, indicative of genetic redundancy. Mammals possess two additional proteinases structurally similar to BMP-1 and mTLD: the genetically distinct mammalian Tolloid-like 1 (mTLL-1) and mTLL-2. Mice lacking the mTLL-1 gene Tll1 are embryonic lethal but have pCP activity levels similar to those of the wild type, suggesting that mTLL-1 might not be an in vivo pCP. In vitro studies have shown BMP-1 and mTLL-1 capable of cleaving Chordin, an extracellular antagonist of BMP signaling, suggesting that these proteases might also serve to modulate BMP signaling and to coordinate the latter with ECM formation. However, in vivo evidence of roles for BMP-1 and mTLL-1 in BMP signaling in mammals is lacking. To remove functional redundancy obscuring the in vivo functions of BMP-1-related proteases in mammals, we here characterize Bmp1 Tll1 doubly null mouse embryos. Although these appear morphologically indistinguishable from Tll1 −/− embryos, biochemical analysis of cells derived from doubly null embryos shows functional redundancy removed to an extent enabling us to demonstrate that (i) products of Bmp1 and Tll1 are responsible for in vivo cleavage of Chordin in mammals and (ii) mTLL-1 is an in vivo pCP that provides residual activity observed in Bmp1 −/− embryos. Removal of functional redundancy also enabled use of Bmp1 −/− Tll1 −/− cells in a proteomics approach for identifying novel substrates of Bmp1 and Tll1 products.

scholarly journals Paracrine Potential of the Human Adipose Tissue-Derived Stem Cells to Modulate Balance between Matrix Metalloproteinases and Their Inhibitors in the Osteoarthritic Cartilage In Vitro

2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
Jaroslav Denkovskij ◽  
Edvardas Bagdonas ◽  
Ilona Kusleviciute ◽  
Zygmunt Mackiewicz ◽  
Ausra Unguryte ◽  
...  
Keyword(s):  
Stem Cells ◽  
Extracellular Matrix ◽  
Adipose Tissue ◽  
Matrix Metalloproteinases ◽  
Cartilage Explants ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Chondrocyte Apoptosis ◽  
Osteoarthritic Cartilage ◽  
Altered Expression

Adipose tissue represents an abundant source of stem cells. Along with anti-inflammatory effects, ASC secrete various factors that may modulate metabolism of extracellular matrix in osteoarthritic (OA) cartilage, suggesting that the presence of ASC could be advantageous for OA cartilage due to the recovery of homeostasis between matrix metalloproteinases (MMPs) and their tissue inhibitors of metalloproteinases (TIMPs). To evaluate these effects, cartilage explants (CE) were cocultured with ASC for 3 and 7 days under stimulation with or without IL-1β. The pattern of gene expression in CE was modified by ASC, including the upregulation of COL1A1 and COL3A1 and the downregulation of MMP13 and COL10A1. The production of MMP-1, MMP-3, and MMP-13 by ASC was not significant; moreover, cocultures with ASC reduced MMP-13 production in CE. In conclusion, active production of TIMP-1, TIMP-2, TIMP-3, IL-6, IL-8, and gelatinases MMP-2 and MMP-9 by ASC may be involved in the extracellular matrix remodelling, as indicated by the altered expression of collagens, the downregulated production of MMP-13, and the reduced chondrocyte apoptosis in the cocultured CE. These data suggest that ASC modulated homeostasis of MMPs/TIMPs in degenerated OA cartilage in vitro and might be favourable in case of the intra-articular application of ASC therapy for the treatment of OA.

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