Spring 2013
The Canadian Institutes of Health Research (CIHR) has awarded UBC Dentistry professor Dieter Brömme, Canada Research Chair in Proteases and Diseases, over $1.14 million for two studies to investigate the role of cathepsins in osteoporosis, arthritis and cardiovascular disease.
Osteoporosis, a disease resulting in loss of bone, affects the lives of millions of Canadians, and is a major burden to health care systems worldwide due to the increasing elderly population. Current treatments, such as hormone replacement therapy or bisphosphonates, have either various side effects or patent expiration issues. Arthritis is caused by an overactive immune system attacking the body’s own tissues—most commonly the joints, and also tendons, bones and ligaments—leading to inflammation, pain and tissue damage.
Just over $583,000 will fund “Mechanisms of Osteoclastic Bone Resorption: Collagenase Activity of Cathepsin K.” This study focuses on cathepsin K as a novel pharmaceutical target for the treatment of osteoporosis and various forms of arthritis. Cathepsin K is a cysteine protease predominantly expressed in osteoclasts, cells which are responsible for the degradation of bone collagen.
Presently, in clinical trials that use inhibitors to block the activity of the protease cathepsin K, there is an improvement in the quality of bone, but the overall results still fall short due to off-target and off-site effects. Brömme and his team seek a cathepsin K inhibitor that will inhibit the osteoclast-mediated collagen degradation in bone but will not inhibit or otherwise affect the protease’s activities in other types of cells.
“Our objective is to understand the cathepsin K-specific mechanism of collagen degradation, and understand how to exploit this knowledge in developing novel and highly selective cathepsin inhibitors. We also need to elucidate potential off-target and off-site inhibition effects and determine how to avoid them,” Brömme says.
There is a strong correlation between osteoporosis and calcification, the formation of mineral deposits in arteries. Arterial calcification makes blood vessels brittle and restricts blood flow, and is predictive of cardiovascular diseases like heart attack and stroke, which are the main causes of death in Canada. Brömme’s other study, which received just over $556,000 from the CIHR, is titled “The Role of Cathepsins in Vascular Calcification.” As Brömme points out, little is known about the mechanism of calcification and whether the degradation of the matrix leads to mineralization, or vice versa. The calcification may actually be a kind of protective response that has gone out of control, thus causing the vessel destruction.
Calcification mainly happens in the extracellular matrix of blood vessels. The primary extracellular matrix components, elastin and collagen, are both heavily degraded by cathepsins during hardening of the arteries (atherosclerosis), and also during ballooning of blood vessels (aneurisms). Here, too, cathepsin K is of particular interest to Brömme. He and others have demonstrated that this enzyme is critically involved in both bone degradation and weakening of the arteries, though its specific c role in calcification is unknown. Since the introduction of a cathepsin K inhibitor is beneficial in the case of osteoporosis, would it also be beneficial to prevent calcification and resulting arterial degradation? Brömme predicts so.