Targeting a single function of the multifunctional matrix metalloprotease MT1-MMP: impact on lymphangiogenesis

TY - JOUR

T1 - Targeting a single function of the multifunctional matrix metalloprotease MT1-MMP

T2 - impact on lymphangiogenesis

AU - Ingvarsen, Signe

AU - Porse, Astrid

AU - Erpicum, Charlotte

AU - Maertens, Ludovic

AU - Jürgensen, Henrik J

AU - Madsen, Daniel H

AU - Melander, Maria C

AU - Gårdsvoll, Henrik

AU - Høyer-Hansen, Gunilla

AU - Noel, Agnès

AU - Holmbeck, Kenn

AU - Engelholm, Lars H

AU - Behrendt, Niels

PY - 2013/4/12

Y1 - 2013/4/12

N2 - The group of matrix metalloproteases (MMPs) is responsible for multiple processes of extracellular matrix remodeling in the healthy body but also for matrix and tissue destruction during cancer invasion and metastasis. The understanding of the contributions from each individual MMP, both in healthy and pathological events, has been complicated by the lack of specific inhibitors and the fact that some of the potent MMPs are multifunctional enzymes. These factors have also hampered the setup of therapeutic strategies targeting MMP activity. A tempting target is the membrane-associated MT1-MMP, which has well-documented importance in matrix degradation but which takes part in more than one pathway in this regard. In this report, we describe the selective targeting of a single function of this enzyme by means of a specific monoclonal antibody against MT1-MMP, raised in an MT1-MMP knock-out mouse. The antibody blocks the enzyme ability to activate proMMP-2 without interfering with the collagenolytic function or the general proteolytic activity of MT1-MMP. Using this antibody, we have shown that the MT1-MMP-catalyzed activation of proMMP-2 is involved in the outgrowth of cultured lymphatic endothelial cells in a collagen matrix in vitro, as well as in lymphatic vessel sprouting assayed ex vivo. This is the first example of the complete inactivation of a single function of a multifunctional MMP and the use of this strategy to pursue its role.

AB - The group of matrix metalloproteases (MMPs) is responsible for multiple processes of extracellular matrix remodeling in the healthy body but also for matrix and tissue destruction during cancer invasion and metastasis. The understanding of the contributions from each individual MMP, both in healthy and pathological events, has been complicated by the lack of specific inhibitors and the fact that some of the potent MMPs are multifunctional enzymes. These factors have also hampered the setup of therapeutic strategies targeting MMP activity. A tempting target is the membrane-associated MT1-MMP, which has well-documented importance in matrix degradation but which takes part in more than one pathway in this regard. In this report, we describe the selective targeting of a single function of this enzyme by means of a specific monoclonal antibody against MT1-MMP, raised in an MT1-MMP knock-out mouse. The antibody blocks the enzyme ability to activate proMMP-2 without interfering with the collagenolytic function or the general proteolytic activity of MT1-MMP. Using this antibody, we have shown that the MT1-MMP-catalyzed activation of proMMP-2 is involved in the outgrowth of cultured lymphatic endothelial cells in a collagen matrix in vitro, as well as in lymphatic vessel sprouting assayed ex vivo. This is the first example of the complete inactivation of a single function of a multifunctional MMP and the use of this strategy to pursue its role.

U2 - 10.1074/jbc.M112.447169

DO - 10.1074/jbc.M112.447169

M3 - Journal article

C2 - 23413031

SN - 0021-9258

VL - 288

SP - 10195

EP - 10204

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

IS - 15

ER -