Abstract
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.
Highlights
An imbalance between bone formation and resorption can cause various bone diseases such as osteoporosis, certain forms of arthritis, and Paget disease
Since fluorescence polarization is considered to be proportional to the molecular size, an increasing polarization indicates the binding of cathepsin K to Chondroitin 4-sulfate (C4-S)*
Saturation of the polarization signal was reached at tory effect on the collagenolytically active cathepsin K/C4-S complex (Fig. 2A)
Summary
An imbalance between bone formation and resorption can cause various bone diseases such as osteoporosis, certain forms of arthritis, and Paget disease. It was recently demonstrated that bone- and cartilage-resident glycosaminoglycans such as chondroitin sulfate (C4-S) enhance degradation of type I collagens by cathepsin K [11], suggesting a specific interaction between C4-S and cathepsin K. These glycosaminoglycans are released as peptidyl glycosaminoglycans by cathepsin activity from proteoglycans such as aggregan and can subsequently form the complex [12]. We assume that compounds which interfere with the formation of an active cathepsin K/C4-S complex and/or its binding to collagen would only inhibit collagen breakdown without affecting the proteolytic function of the enzyme. The impact of a disturbed carbohydrate-protein interaction
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