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J. Biol. Chem., Vol. 279, Issue 37, 39105-39114, September 10, 2004

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A Theoretical Model of Type I Collagen Proteolysis by Matrix Metalloproteinase (MMP) 2 and Membrane Type 1 MMP in the Presence of Tissue Inhibitor of Metalloproteinase 2^*

Emmanouil D. Karagiannis and Aleksander S. Popel

From the Department of Biomedical Engineering, Johns Hopkins University, School of Medicine, Baltimore, Maryland 21205

One well documented family of enzymes responsible for the proteolytic processes that occur in the extracellular matrix is the soluble and membrane-associated matrix metalloproteinases. Here we present the first theoretical model of the biochemical network describing the proteolysis of collagen I by matrix metalloproteinases 2 (MMP2) and membrane type 1 matrix metalloproteinases (MT1-MMP) in the presence of the tissue inhibitor of metalloproteinases 2 (TIMP2) in a bulk, cell-free, well stirred environment. The model can serve as a tool for describing quantitatively the activation of the MMP2 proenzyme (pro-MMP2), the ectodomain shedding of MT1-MMP, and the collagenolysis arising from both of the enzymes. We show that pro-MMP2 activation, a process that involves a trimer formation of the proenzyme with TIMP2 and MT1-MMP, is suppressed at high inhibitor levels and paradoxically attains maximum only at intermediate TIMP2 concentrations. We also calculate the conditions for which pro-MMP2 activation is maximal. Furthermore we demonstrate that the ectodomain shedding of MT1-MMP can serve as a mechanism controlling the MT1-MMP availability and therefore the pro-MMP2 activation. Finally the proteolytic synergism of MMP2 and MT1-MMP is introduced and described quantitatively. The model provides us a tool to determine the conditions under which the synergism is optimized. Our approach is the first step toward a more complete description of the proteolytic processes that occur in the extracellular matrix and include a wider spectrum of enzymes and substrates as well as naturally occurring or artificial inhibitors.

Received for publication, April 1, 2004 , and in revised form, July 7, 2004.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains the system of ordinary nonlinear differential equations describing the time evolution of the various species concentrations.

To whom correspondence should be addressed. Tel.: 410-955-1787; Fax: 410-614-8796; E-mail: ekaragia{at}bme.jhu.edu.

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