Bone homeostasis is a complex process and requires a balance between bone formation and resorption. Cathepsin K is a collagenase which is highly expressed in bone resorbing cells and its deficiency leads to pycnodysostosis, a rare disease characterized by a decrease in bone resorption. Osteoporosis, a disease in which bones become fragile and more likely to fracture due to excessive resorption, affect more than 10 million individuals in the U.S.. Current approaches to suppress bone loss are focused on anti-resorptive therapies have failed in clinical trials due to off target effects. These therapies have mainly used warheads to trap the active site of cathepsin K in order to inhibit the collagenase activity.
Dr. Bromme discovered that glycosaminoglycans (GAGs) form a complex with cathepsin K and that GAGs which are predominantly expressed in bone 
and cartilage, such as chondroitin and keratan sulfates, enhance the collagenolytic activity of cathepsin K (Fig A). This complex is unique among human papain-like cysteine proteases and the formation of the complex does not involve the active site of cathepsin K (Fig B).
These findings suggest that inhibiting cathepsin K-GAGs interaction is a novel alternative to current strategies for inhibiting cathepsin K function without substantial interference in other biologically relevant activities. The discovery can be applied in the development of new therapies for diseases like osteoporosis and rheumatoid arthritis.
Current Development Status
- In vitro characterization of the collagenolytic cathepsin K activity and its regulation by glycosaminoglycans
Applications
- Osteoporosis
- Rheumatoid arthritis
- Pycnodysostosis
Advantages
- Strategy focused on cathepsin K-GAGs interaction to inhibit the collagenase activity in a specific and independent manner from strategies to trap the active site in cathepsin K should reduce side effects associated with targeting the active site of cathepsin K
Publications
- Nallaseth. “The Role of Basic Amino Acid Surface Clusters on the Collagenase Activity of Cathepsin K.” (2013) Biochem. 52(44):7742-7752
- Li. “Structure-Activity Analysis of Cathepsin K/Chondroitin 4-Sulfate Interactions.” (2008) J. Mol. Biol. 383:78-91
- Selent. “Selective Inhibition of the Collagenase Activity of Cathepsin K.” (2007) J. Biol. Chem. 282:16492-16501
- Li. “A novel allosteric mechanism in the cysteine peptidase cathepsin K discovered by computational methods.” (2004) J. Biol. Chem. 279:5470-5479
- Wang. “Cathepsin K inhibitor-polymer conjugates: potential drugs for the treatment of osteoporosis and rheumatoid arthritis.” (2004) Int. J. Pharm. 11;277(1-2):73-9
Patent Status
- International Application PCT/US02/30198 filed September 24, 2002
- Status: Published. International Publication No. WO 2003/041635
Contact Information
Lisa Placanica, Ph.D., CLP
Business Development Director
Mount Sinai Innovation Partners | Icahn School of Medicine at Mount Sinai
Phone: 646.605.7325