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J. Biol. Chem., Vol. 282, Issue 22, 16492-16501, June 1, 2007

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Selective Inhibition of the Collagenase Activity of Cathepsin K^*

Jana Selent, Jadwiga Kaleta, Zhenqiang Li, Gilles Lalmanach^¶, and Dieter Brömme¹

From the Department of Oral Biological and Medical Sciences, Faculty of Dentistry and the Center for Blood Research, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada, Bristol Myers Squibb, Pennington, New Jersey 08534, and the ^¶INSERM U618, Protéases et Vectorisation Pulmonaires/IFR 135 "Imagerie Fonctionnelle," Université François Rabelais, FacultédeMédecine, 10 Boulevard Tonnellé, F-37032 Tours Cédex, France

Cathepsin K, the main bone degrading protease, and chondroitin 4-sulfate (C4-S) form a complex with enhanced collagenase activity. In this report, we demonstrate the specific inhibition of the collagenase activity of cathepsin K by negatively charged polymers without affecting the overall proteolytic activity of the protease. Three different mechanisms to interfere with cathepsin-catalyzed collagen degradation are discussed: 1) inhibition of the formation of the cathepsin K/C4-S complex, 2) inhibition of the attachment of C4-S to collagen, and 3) masking of the collagenase cleavage sites in collagen. By targeting these interaction sites, collagen degradation can be modulated while the non-collagenolytic activities of cathepsin K remain intact. The main inhibitory effect on collagen degradation is due to the impeding effect on the active cathepsin K/C4-S complex. Essential structural elements in the inhibitor molecules are negative charges which compete with the sulfate groups of C4-S in the cathepsin K/C4-S complex. The inhibitory effect can be controlled by length and charge of the polymers. Longer negatively charged polymers (e.g. polyglutamates, oligonucleotides) tend to inhibit all three mechanisms, whereas shorter ones preferentially affect the cathepsin K/C4-S complex.

Received for publication, January 9, 2007 , and in revised form, March 15, 2007.

^* This work was supported in part by National Institutes of Health Grants AR 48669 and DK 072070. 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.

¹ Supported by a Canada Research Chair award. A Canada Research Chair in Proteases and Diseases. To whom correspondence should be addressed: University of British Columbia, Faculty of Dentistry, Dept. of Oral and Biological Sciences, 2350 Health Sciences Mall, Vancouver V6J 1Z3, Canada. Tel.: 604-822-1787; E-mail: dbromme{at}interchange.ubc.ca.

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