Grant: Operating Grant

Osteoporosis affects the lives of millions of Canadians and is a major burden to health care systems worldwide due to an increasing elderly population. Typical treatment regimes such as hormone replacement therapy or bisphosphonates have either various side effects or patent expiration issues. We and others have identified cathepsin K, a cysteine protease predominantly expressed in osteoclasts and responsible for the degradation of bone collagen, as a novel pharmaceutical target for the treatment of osteoporosis and various forms of arthritis. Active site directed inhibitors which block the total proteolytic activity of this protease are presently in several advanced clinical trials and proved highly effective in improving the quality of bone. However, major problems of this approach are off-target and off-site effects which caused the termination of at least two clinical trials. A highly effective cathepsin K inhibitor should only inhibit the osteoclast mediated collagen degradation in bone without affecting the protease's activities in other cell types and avoid the inhibition of related proteases with other functions. This clearly indicates the need for a better understanding of the biology and mechanism of action of cathepsin K. Our laboratory is interested in the elucidation of mechanisms of specific and disease-related matrix protein degradation by cathepsins, their biological functions and the development of novel inhibitors based on their specific mechanism and function in health and disease. Our objective is to understand the cathepsin K specific mechanism of collagen degradation, how to exploit this knowledge in developing novel and highly selective inhibitors, as well as the elucidation of potential off target and off-site inhibition effects and how to avoid them. This understanding will help to develop very needed novel and more specific types of treatment methods for various erosive skeletal diseases.