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Papers In Press, published online ahead of print January 23, 2001
J. Biol. Chem, 10.1074/jbc.C000848200
Submitted on November 30, 2000
Revised on January 17, 2001
Accepted on January 22, 2001
Biochemistry and Molecular Biology, University of Miami, Miami, FL 33101
Corresponding Author: kbrew{at}molbio.med.miami.edu
The proteoglycan, aggrecan, is an important major component of cartilage matrix that gives articular cartilage the ability to withstand compression. Increased breakdown of aggrecan is associated with the development of arthritis, and is considered to be catalyzed by aggrecanases, members of the ADAM-TS family of metalloproteinases. Four endogenous tissue inhibitors of metalloproteinases (TIMPs) regulate the activities of functional matrix metalloproteinases (MMPs), enzymes that degrade most components of connective tissue, but no endogenous factors responsible for the regulation of aggrecanases have been found. We show here that the N-terminal inhibitory domain of TIMP-3, a member of the TIMP family that has distinct functional properties from other TIMPs, is a strong inhibitor of human aggrecanases 1 and 2 with Ki values in the subnanomolar range. This truncated inhibitor, that lacks the C-terminal domain responsible for interactions with molecules other than active metalloproteinases, is produced at high yield by bacterial expression and folding from inclusion bodies. This provides a starting-point for developing a biologically available aggrecanase inhibitor suitable for the treatment of arthritis.
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