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MBC in Press, published online ahead of print September 13, 2006
Mol. Biol. Cell 10.1091/mbc.E06-06-0486

A more recent version of this article appeared on November 1, 2006 Originally published as MBC in Press, 10.1091/mbc.E06-06-0486 on October 18, 2006 Originally published as MBC in Press, 10.1091/mbc.E06-06-0486 on September 15, 2006
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Submitted on June 2, 2006
Revised on July 31, 2006
Accepted on August 31, 2006

A Critical Role for MT1-MMP in Collagen Phagocytosis

Hyejin Lee,*{dagger} Christopher M. Overall,*{ddagger} Christopher A. McCulloch,* and Jaro Sodek*{dagger}

*Canadian Institutes of Health Research Group in Matrix Dynamics, Faculty of Dentistry, and the {dagger}Department of Biochemistry, Faculty of Medicine, University of Toronto, Toronto, Ontario M5S 3E2, Canada; {ddagger}University of British Columbia Centre for Blood Research, Vancouver, British Columbia V67 1Z3, Canada

Monitoring Editor: Asma Nusrat

Degradation of collagen is important for the physiological remodelling of connective tissues during growth and development, as well as in wound healing, inflammatory diseases and cancer cell invasion. In remodelling adult tissues, degradation of collagen occurs primarily through a phagocytic pathway. However, while various steps in the phagocytic pathway have been characterized, the enzyme required to initially fragment collagen fibrils for subsequent phagocytosis has not been identified. We have used laser confocal microscopy, TEM and biochemical assays to show that human fibroblasts initiate degradation of collagen through the collagenase activity of the membrane-bound metalloproteinase, MT1-MMP. Degradation of natural and reconstituted collagen substrates correlated with the expression of MT1-MMP, which was localized at sites of collagen cleavage at the surface of the cells and also within the cells, while collagen degradation was totally abrogated when MT1-MMP expression was blocked by siRNA treatment. In contrast to MT1-MMP, the gelatinolytic activity of MMP-2 was not required for collagen phagocytosis. These studies demonstrate a pivotal role of catalytically active MT1-MMP in preparing collagen fibrils for phagocytic degradation.

Address correspondence to: Jaro Sodek (jaro.sodek{at}utoronto.ca)




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