Bone morphogenic protein-7 inhibits progression of chronic renal fibrosis associated with two genetic mouse models

2003 ◽  
Vol 285 (6) ◽  
pp. F1060-F1067 ◽  
Author(s):  
Michael Zeisberg ◽  
Cindy Bottiglio ◽  
Navin Kumar ◽  
Yohei Maeshima ◽  
Frank Strutz ◽  
...  
Keyword(s):  
Mouse Models ◽  
Renal Injury ◽  
Renal Fibrosis ◽  
Type I Collagen ◽  
Chronic Renal Disease ◽  
Bone Morphogenic Protein ◽  
Matrix Metalloproteinase 2 ◽  
Type I ◽  
Protective Function ◽  
Bone Morphogenic Protein 7

Tubulointerstitial fibrosis is a hallmark feature of chronic renal injury. Specific therapies to control the progression of renal fibrosis toward end-stage renal failure are limited. Previous studies have demonstrated that expression of endogenous bone morphogenic protein-7 (BMP-7) is reduced in the kidneys of several inducible mouse models of acute and chronic renal disease and that administration of exogenous recombinant human BMP-7 (rhBMP-7) has a beneficial effect on kidney function. Here we report that treatment with rhBMP-7 leads to improved renal function, histology, and survival in mice deficient in the α3-chain of type IV collagen and MRL/MpJ lpr/lpr lupus mice, two genetic models for chronic renal injury and fibrosis. Such therapeutic benefit is also associated with a significant decrease in the expression of profibrotic molecules, such as type I collagen and fibronectin, in renal fibroblasts. Additionally, rhBMP-7 induces expression of active matrix metalloproteinase-2, which is potentially important for removal of fibrotic matrix. Collectively, these studies provide further evidence for rhBMP-7 as an important bone-associated protein with protective function against renal pathology.

Type I collagen from sea cucumber (Stichopus japonicus) and the role of matrix metalloproteinase-2 in autolysis

2021 ◽  
Vol 41 ◽  
pp. 100959
Author(s):  
Long-Jie Yan ◽  
Le-Chang Sun ◽  
Kai-Yuan Cao ◽  
Yu-Lei Chen ◽  
Ling-Jing Zhang ◽  
...  
Keyword(s):  
Matrix Metalloproteinase ◽  
Sea Cucumber ◽  
Type I Collagen ◽  
Matrix Metalloproteinase 2 ◽  
Type I ◽  
Stichopus Japonicus

scholarly journals Molecular Mechanism for Connective Tissue Destruction by Dipeptidyl Aminopeptidase IV Produced by the Periodontal Pathogen Porphyromonas gingivalis

2005 ◽  
Vol 73 (5) ◽  
pp. 2655-2664 ◽  
Author(s):  
Yumi Kumagai ◽  
Hisao Yagishita ◽  
Ayako Yajima ◽  
Tatsuya Okamoto ◽  
Kiyoshi Konishi
Keyword(s):  
Connective Tissue ◽  
Molecular Mechanism ◽  
Porphyromonas Gingivalis ◽  
Type I Collagen ◽  
Plasmid Vector ◽  
Periodontal Pathogen ◽  
Matrix Metalloproteinase 2 ◽  
Type I ◽  
Tissue Destruction ◽  
Dipeptidyl Aminopeptidase

ABSTRACT Porphyromonas gingivalis is a pathogen associated with adult periodontitis. It produces dipeptidyl aminopeptidase IV (DPPIV), which may act as a virulence factor by contributing to the degradation of connective tissue. We investigated the molecular mechanism by which DPPIV contributes to the destruction of connective tissue. DPPIV itself did not show gelatinase or collagenase activity toward human type I collagen, but it promoted the activity of the host-derived matrix metalloproteinase 2 (MMP-2) (gelatinase) and MMP-1 (collagenase). DPPIV bound to fibronectin and mediated the adhesion of P. gingivalis to fibronectin. Mutant DPPIV with catalytic Ser mutagenized to Ala (DPPSA) did not accelerate the degradation of collagen and gelatin by MMPs but retained fibronectin-binding activity. The adhesion of human gingival fibroblasts and NIH 3T3 cells to fibronectin was inhibited by DPPIV. Strain 4351ADPPSA exhibited an intermediate level of virulence in mice, between that of the strain expressing wild-type DPPIV (4351ADPP) and that of the strain harboring only the plasmid vector (4351AVEC). It is suggested that both activity promoting the degradation of collagen and gelatin and binding to fibronectin are required for full virulence. These results reveal novel biological functions of DPPIV and suggest a pathological role in the progression of periodontitis.

scholarly journals Type I collagen is a genetic modifier of matrix metalloproteinase 2 in murine skeletal development

2007 ◽  
Vol 236 (6) ◽  
pp. 1683-1693 ◽  
Author(s):  
Mikala Egeblad ◽  
H.-C. Jennifer Shen ◽  
Danielle J. Behonick ◽  
Lisa Wilmes ◽  
Alexandra Eichten ◽  
...  
Keyword(s):  
Matrix Metalloproteinase ◽  
Type I Collagen ◽  
Skeletal Development ◽  
Genetic Modifier ◽  
Matrix Metalloproteinase 2 ◽  
Type I

Ciprofloxacin up-regulates tendon cells to express matrix metalloproteinase-2 with degradation of type I collagen

2010 ◽  
Vol 29 (1) ◽  
pp. 67-73 ◽  
Author(s):  
Wen-Chung Tsai ◽  
Chih-Chin Hsu ◽  
Carl P.C. Chen ◽  
Hsiang-Ning Chang ◽  
Alice M.K. Wong ◽  
...  
Keyword(s):  
Matrix Metalloproteinase ◽  
Type I Collagen ◽  
Matrix Metalloproteinase 2 ◽  
Type I ◽  
Tendon Cells

Protease-activated receptor 1 knockout reduces experimentally induced liver fibrosis

2008 ◽  
Vol 294 (1) ◽  
pp. G226-G235 ◽  
Author(s):  
Anne Rullier ◽  
Jennifer Gillibert-Duplantier ◽  
Pierre Costet ◽  
Gaëlle Cubel ◽  
Valérie Haurie ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Blood Coagulation ◽  
Type I Collagen ◽  
Collagen Matrix ◽  
Matrix Metalloproteinase 2 ◽  
Type I ◽  
Mrna Levels ◽  
Protease Activated Receptors ◽  
Thrombin Inhibition ◽  
Β Receptor

Thrombin inhibition protects against liver fibrosis. However, it is not known whether the thrombin profibrogenic effect is due to effects on blood coagulation or to signaling via protease-activated receptors (PARs). We took advantage of the lack of blood coagulation defects in PAR-1-knockout mice. Acute carbon tetrachloride (CCl4) toxicity was similar in wild-type (WT), PAR-1−/−, and PAR-1+/−mice as judged by aminotransferase levels, area of liver necrosis, and liver peroxidation measured by Fourier-transformed infrared spectroscopy. Fifteen mice/group received CCl4or its solvent for 6 wk (300 μl/kg, 3 times a week). Fibrosis area was increased 10-fold by CCl4treatment in WT mice. PAR-1 deficiency protected against fibrosis, with 36% and 56% decrease in PAR-1+/−and PAR-1−/−mice, respectively ( P < 0.001). Similar results were obtained for area of activated fibrogenic cells (64% and 79% decrease in PAR-1+/−and PAR-1−/−mice, respectively, P < 0.001). These findings were corroborated by measurements of type I collagen, matrix metalloproteinase-2, and PDGF-β receptor mRNA levels. There was also a significant decrease in T lymphocyte infiltration in PAR-1-deficient mice. Altogether, these results suggest that thrombin profibrogenic effects are independent of effects on blood coagulation and are instead due to direct effects on fibrogenic cells and possibly on T lymphocytes.

scholarly journals Altered bleomycin-induced lung fibrosis in osteopontin-deficient mice

2004 ◽  
Vol 286 (6) ◽  
pp. L1311-L1318 ◽  
Author(s):  
Jeffrey S. Berman ◽  
David Serlin ◽  
Xinfang Li ◽  
Geoffrey Whitley ◽  
John Hayes ◽  
...  
Keyword(s):  
Lung Fibrosis ◽  
Type I Collagen ◽  
Transforming Growth Factor ◽  
Matrix Metalloproteinase 2 ◽  
Mouse Lung ◽  
Matricellular Protein ◽  
Type Iii Collagen ◽  
Type I ◽  
Osteopontin Expression ◽  
Collagen Expression

Osteopontin is a multifunctional matricellular protein abundantly expressed during inflammation and repair. Osteopontin deficiency is associated with abnormal wound repair characterized by aberrant collagen fibrillogenesis in the heart and skin. Recent gene microarray studies found that osteopontin is abundantly expressed in both human and mouse lung fibrosis. Macrophages and T cells are known to be major sources of osteopontin. During lung fibrosis, however, osteopontin expression continues to increase when inflammation has receded, suggesting alternative sources of ostepontin during this response. In this study, we demonstrate immunoreactivity for osteopontin in lung epithelial and inflammatory cells in human usual interstitial pneumonitis and murine bleomycin-induced lung fibrosis. After treatment with bleomycin, osteopontin-null mice develop lung fibrosis characterized by dilated distal air spaces and reduced type I collagen expression compared with wild-type controls. There is also a significant decrease in levels of active transforming growth factor-β1 and matrix metalloproteinase-2 in osteopontin null mice. Type III collagen expression and total collagenase activity are similar in both groups. These results demonstrate that osteopontin expression is associated with important fibrogenic signals in the lung and that the epithelium may be an important source of osteopontin during lung fibrosis.

scholarly journals Inhibition of MMP-2 gelatinolysis by targeting exodomain–substrate interactions

2007 ◽  
Vol 406 (1) ◽  
pp. 147-155 ◽  
Author(s):  
Xiaoping Xu ◽  
Zhihua Chen ◽  
Yao Wang ◽  
Lynda Bonewald ◽  
Bjorn Steffensen
Keyword(s):  
Binding Site ◽  
Type I Collagen ◽  
Matrix Metalloproteinase 2 ◽  
Type I ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Collagen Binding ◽  
Collagen Peptides ◽  
Collagen Chain ◽  
Hydrolysis Of

MMP-2 (matrix metalloproteinase 2) contains a CBD (collagen-binding domain), which is essential for positioning gelatin substrate molecules relative to the catalytic site for cleavage. Deletion of the CBD or disruption of CBD-mediated gelatin binding inhibits gelatinolysis by MMP-2. To identify CBD-binding sites on type I collagen and collagen peptides with the capacity to compete CBD binding of gelatin and thereby inhibit gelatinolysis by MMP-2, we screened a one-bead one-peptide combinatorial peptide library with recombinant CBD as bait. Analyses of sequences from the CBD-binding peptides pointed to residues 715–721 in human α1(I) collagen chain as a binding site for CBD. A peptide (P713) including this collagen segment was synthesized for analyses. In SPR (surface plasmon resonance) assays, the CBD and MMP-2E404A, a catalytically inactive MMP-2 mutant, both bound immobilized P713 in a concentration-dependent manner, but not a scrambled control peptide. Furthermore, P713 competed gelatin binding by the CBD and MMP-2E404A. In control assays, neither of the non-collagen binding alkylated CBD or MMP-2 with deletion of CBD (MMP-2ΔCBD) bound P713. Consistent with the exodomain functions of the CBD, P713 inhibited ∼90% of the MMP-2 gelatin cleavage, but less than 20% of the MMP-2 activity on a peptide substrate (NFF-1) which does not require the CBD for cleavage. Confirming the specificity of the inhibition, P713 did not alter MMP-2ΔCBD or MMP-8 activities. These experiments identified a CBD-binding site on type I collagen and demonstrated that a corresponding synthetic peptide can inhibit hydrolysis of type I and IV collagens by competing CBD-mediated gelatin binding to MMP-2.

miR-378 reduces mesangial hypertrophy and kidney tubular fibrosis via MAPK signalling

2017 ◽  
Vol 131 (5) ◽  
pp. 411-423 ◽  
Author(s):  
Bo Wang ◽  
Kevin Yao ◽  
Andrea F. Wise ◽  
Ricky Lau ◽  
Hsin-Hui Shen ◽  
...  
Keyword(s):  
Type Iv Collagen ◽  
Type I Collagen ◽  
Transforming Growth Factor ◽  
Mesangial Cell ◽  
Quantitative Polymerase Chain Reaction ◽  
Locked Nucleic Acid ◽  
Type I ◽  
Protective Function ◽  
Type Iv ◽  
Tgf Β1

The regulatory role of a novel miRNA, miR-378, was determined in the development of fibrosis through repression of the MAPK1 pathway, miR-378 and fibrotic gene expression was examined in streptozotocin (STZ)-induced diabetic mice at 18 weeks or in unilateral ureteral obstruction (UUO) mice at 7 days. miR-378 transfection of proximal tubular epithelial cells, NRK52E and mesangial cells was assessed with/without endogenous miR-378 knockdown using the locked nucleic acid (LNA) inhibitor. NRK52E cells were co-transfected with the mothers against decapentaplegic homolog 3 (SMAD3) CAGA reporter and miR-378 in the presence of transforming growth factor-β (TGF-β1) was assessed. Quantitative polymerase chain reaction (qPCR) showed a significant reduction in miR-378 (P<0.05) corresponding with up-regulated type I collagen, type IV collagen and α-smooth muscle actin (SMA) in kidneys of STZ or UUO mice, compared with controls. TGF-β1 significantly increased mRNA expression of type I collagen (P<0.05), type IV collagen (P<0.05) and α-SMA (P<0.05) in NRK52E cells, which was significantly reduced (P<0.05) following miR-378 transfection and reversed following addition of the LNA inhibitor of endogenous miR-378. Overexpression of miR-378 inhibited mesangial cell expansion and proliferation in response to TGF-β1, with LNA–miR-378 transfection reversing this protective effect, associated with cell morphological alterations. The protective function of MAPK1 on miR-378 was shown in kidney cells treated with the MAPK1 inhibitor, selumetinib, which inhibited mesangial cell hypertrophy in response to TGF-β1. Taken together, these results suggest that miR-378 acts via regulation of the MAPK1 pathway. These studies demonstrate the protective function of MAPK1, regulated by miR-378, in the induction of kidney cell fibrosis and mesangial hypertrophy.

scholarly journals Matrix metalloproteinase-2 governs lymphatic vessel formation as an interstitial collagenase

Blood ◽  
2012 ◽  
Vol 119 (21) ◽  
pp. 5048-5056 ◽  
Author(s):  
Benoit Detry ◽  
Charlotte Erpicum ◽  
Jenny Paupert ◽  
Silvia Blacher ◽  
Catherine Maillard ◽  
...  
Keyword(s):  
Matrix Metalloproteinase ◽  
Lymphatic Vessel ◽  
Type I Collagen ◽  
3D Culture ◽  
Matrix Composition ◽  
Matrix Metalloproteinase 2 ◽  
Type I ◽  
Vessel Formation

Abstract Lymphatic dysfunctions are associated with several human diseases, including lymphedema and metastatic spread of cancer. Although it is well recognized that lymphatic capillaries attach directly to interstitial matrix mainly composed of fibrillar type I collagen, the interactions occurring between lymphatics and their surrounding matrix have been overlooked. In this study, we demonstrate how matrix metalloproteinase (MMP)–2 drives lymphatic morphogenesis through Mmp2-gene ablation in mice, mmp2 knockdown in zebrafish and in 3D-culture systems, and through MMP2 inhibition. In all models used in vivo (3 murine models and thoracic duct development in zebrafish) and in vitro (lymphatic ring and spheroid assays), MMP2 blockage or down-regulation leads to reduced lymphangiogenesis or altered vessel branching. Our data show that lymphatic endothelial cell (LEC) migration through collagen fibers is affected by physical matrix constraints (matrix composition, density, and cross-linking). Transmission electron microscopy and confocal reflection microscopy using DQ-collagen highlight the contribution of MMP2 to mesenchymal-like migration of LECs associated with collagen fiber remodeling. Our findings provide new mechanistic insight into how LECs negotiate an interstitial type I collagen barrier and reveal an unexpected MMP2-driven collagenolytic pathway for lymphatic vessel formation and morphogenesis.

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