Overexpression of Runx2 directed by the matrix metalloproteinase-13 promoter containing the AP-1 and Runx/RD/Cbfa sites alters bone remodeling in vivo

To examine the role of matrilysin (MAT), an epithelial cell-specific matrix metalloproteinase, in the normal development and function of reproductive tissues, we generated transgenic animals that overexpress MAT in several reproductive organs. Three distinct forms of human MAT (wild-type, active, and inactive) were placed under the control of the murine mammary tumor virus promoter/enhancer. Although wild-type, active, and inactive forms of the human MAT protein could be produced in an in vitro culture system, mutations of the MAT cDNA significantly decreased the efficiency with which the MAT protein was produced in vivo. Therefore, animals carrying the wild-type MAT transgene that expressed high levels of human MAT in vivo were further examined. Mammary glands from female transgenic animals were morphologically normal throughout mammary development, but displayed an increased ability to produce β-casein protein in virgin animals. In addition, beginning at approximately 8 mo of age, the testes of male transgenic animals became disorganized with apparent disintegration of interstitial tissue that normally surrounds the seminiferous tubules. The disruption of testis morphology was concurrent with the onset of infertility. These results suggest that overexpression of the matrix-degrading enzyme MAT alters the integrity of the extracellular matrix and thereby induces cellular differentiation and cellular destruction in a tissue-specific manner.

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Matrix metalloproteinase processing of monocyte chemoattractant proteins generates CC chemokine receptor antagonists with anti-inflammatory properties in vivo

Blood ◽

10.1182/blood.v100.4.1160.h81602001160_1160_1167 ◽

2002 ◽

Vol 100 (4) ◽

pp. 1160-1167 ◽

Cited By ~ 392

Author(s):

G. Angus McQuibban ◽

Jiang-Hong Gong ◽

Julie P. Wong ◽

John L. Wallace ◽

Ian Clark-Lewis ◽

...

Keyword(s):

Matrix Metalloproteinase ◽

Chemokine Receptor ◽

Chemokine Receptors ◽

Leukemic Cell ◽

Proteolytic Processing ◽

Cc Chemokine ◽

Monocyte Chemoattractant ◽

The Matrix

Monocyte chemoattractant protein (MCP)–3 is inactivated upon cleavage by the matrix metalloproteinase (MMP) gelatinase A (MMP-2). We investigated the susceptibility to proteolytic processing of the 4 human MCPs by 8 recombinant MMPs to determine whether MCP-3 is an isolated example or represents a general susceptibility of chemokines to proteolytic inactivation by these important inflammatory proteases. In addition to MMP-2, MCP-3 is efficiently cleaved by membrane type 1 (MT1)–MMP, the cellular activator of MMP-2, and by collagenase-1 and collagenase-3 (MMP-1, MMP-13) and stromelysin-1 (MMP-3). Specificity was shown by absence of cleavage by matrilysin (MMP-7) and the leukocytic MMPs neutrophil collagenase (MMP-8) and gelatinase B (MMP-9). The closely related chemokines MCP-1, MCP-2, and MCP-4 were not cleaved by MMP-2 or MT1-MMP, but were cleaved by MMP-1 and MMP-3 with varying efficiency. MCPs were typically cleaved between residues 4 and 5, but MCP-4 was further processed at Val7-Pro8. Synthetic MCP analogs corresponding to the MMP-cleaved forms bound CC chemokine receptor (CCR)–2 and CCR-3, but lacked chemoattractant activity in pre-B cells transfected with CCR-2 and CCR-3 or in THP-1 monocytic cells, a transformed leukemic cell line. Moreover, the truncated products of MCP-2 and MCP-4, like MCP-3, were potent antagonists of their cognate CC chemokine receptors in transwell cell migration assays in vitro. When they were injected 24 hours after the initiation of carrageenan-induced inflammation in rat paws, their in vivo antagonist activities were revealed by a greater than 66% reduction in inflammatory edema progression after 12 hours. We propose that MMPs have an important role in modulating inflammatory and immune responses by processing chemokines in wound healing and in disease.

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Nucleolin binds specifically to an AP-1 DNA sequence and represses AP1-dependent transactivation of the matrix metalloproteinase-13 gene

Molecular Carcinogenesis ◽

10.1002/mc.20358 ◽

2007 ◽

Vol 47 (1) ◽

pp. 34-46 ◽

Cited By ~ 12

Author(s):

Shaija Samuel ◽

Jean-Claude Twizere ◽

Katherine K. Beifuss ◽

Lori R. Bernstein

Keyword(s):

Matrix Metalloproteinase ◽

Dna Sequence ◽

Matrix Metalloproteinase 13 ◽

The Matrix

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Matrix metalloproteinase 13 is transcriptionally modulated in the spinal cords of salamanders during spinal cord regeneration.

10.31219/osf.io/w9yqt ◽

2020 ◽

Author(s):

Shahan Mamoor

Keyword(s):

Spinal Cord ◽

Matrix Metalloproteinase ◽

Transcriptional Response ◽

Spinal Cord Regeneration ◽

Significant Differential Expression ◽

Matrix Metalloproteinase 13 ◽

Complete Transection ◽

Ability To Regenerate ◽

The Matrix ◽

The Central Nervous System

In nature, there are extraordinary creatures that have the ability to regenerate the spinal cord following a severing injury; these include the axolotl salamander (1, 2, 3, 4). To being to attempt to understand the mechanisms by which this transpires, we studied the transcriptional response to spinal cord trauma in a creature capable of spinal cord regeneration using microarray data (5, 6) from a severing injury model in the axolotl. We observed significant differential expression of the matrix metalloproteinase 13, MMP13, during regeneration of the spinal cord following complete transection. MMP13 is likely one actor in a complex multi-step process by which the central nervous system regenerates itself.

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Runx2 Recruits p300 to Mediate Parathyroid Hormone’s Effects on Histone Acetylation and Transcriptional Activation of the Matrix Metalloproteinase-13 Gene

Molecular Endocrinology ◽

10.1210/me.2008-0217 ◽

2009 ◽

Vol 23 (8) ◽

pp. 1255-1263 ◽

Cited By ~ 30

Author(s):

Christine E. Boumah ◽

Minnkyong Lee ◽

Nagarajan Selvamurugan ◽

Emi Shimizu ◽

Nicola C. Partridge

Keyword(s):

Matrix Metalloproteinase ◽

Histone Acetylation ◽

Transcriptional Activation ◽

Matrix Metalloproteinase 13 ◽

The Matrix

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Statins for the prevention of vein graft stenosis: a role for inhibition of matrix metalloproteinase-9

Biochemical Society Transactions ◽

10.1042/bst0300120 ◽

2002 ◽

Vol 30 (2) ◽

pp. 120-126 ◽

Cited By ~ 30

Author(s):

K. E. Porter ◽

N. A. Turner

Keyword(s):

Matrix Metalloproteinase ◽

Intimal Hyperplasia ◽

Therapeutic Potential ◽

Matrix Metalloproteinase 2 ◽

Neointima Formation ◽

Graft Stenosis ◽

The Matrix ◽

And Migration ◽

Proliferation And Migration

Saphenous vein (SV) grafts are commonly used to bypass coronary arteries that are diseased due to atherosclerosis. However, the development of intimal hyperplasia in such grafts can lead to patency-threatening stenosis and re-occlusion of the vessel. The proliferation and migration of smooth muscle cells (SMC) play key roles in the development of intimal hyperplasia, and an agent that inhibits both of these processes therefore has therapeutic potential. A prerequisite for SMC proliferation and migration in vivo is degradation of the basement membrane, achieved by secretion of the matrix-degrading gelatinases matrix metalloproteinase-2 (MMP-2) and MMP-9. Statins are cholesterol-lowering drugs that also have direct effects on SMC function. Here we report that neointima formation in organ-cultured human SV segments is inhibited by simvastatin, an effect that is associated with reduced MMP-9 activity. Additionally, our work shows that simvastatin not only inhibits proliferation, but importantly also inhibits invasion (migration through a matrix barrier), of cultured human SV SMC. Thus simvastatin treatment appears to inhibit neointima formation as a result of combined inhibition of SMC proliferation and invasion. The potential intracellular mechanisms by which statins affect SMC proliferation and migration, and thus attenuate intimal hyperplasia, are discussed, with particular emphasis on the role of MMP-9.

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