30 Aug New Approach Could Lead To Osteoporosis Drugs With Fewer Side Effects
MedicalResearch.com Interview with:
Dr. Bromme
Dieter Bromme, Ph.D.
Professor and Canada Research Chair
The University of British Columbia Faculty of Dentistry
Vancouver, BC
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: Every three seconds somebody will fracture a bone because of osteoporosis. Several treatments are available to slow down bone loss but all of them have shortcomings ranging from poor bone quality to various side effects. Thus new treatment strategies and novel drug targets are needed that promise efficacy without significant adverse reactions.
One of the novel promising targets was cathepsin K, a protease solely responsible for the degradation of our organic bone matrix. Major efforts and funds were spent by the pharmaceutical industry to develop potent and selective cathepsin K inhibitors. These inhibitors were highly effective in preserving bone in clinical trials. Despite the good news, cathepsin K inhibitors were never approved because of various non-skeletal side effects. We hypothesized that these side effects are not caused by off-target effects (drugs react with undesired targets) but by on-target effects. Most drugs that target enzymes are active site-directed compounds and thus will stop the entire activity of the target enzyme. If the target is a multifunctional enzyme, safety problems are preprogrammed. Based on our studies to understand the molecular mechanism of collagen degradation by cathepsin K, we developed the concept of ectosteric enzyme inhibition, which allowed us to identify highly selective collagenase inhibitors of this protease.
In our study, we used a red sage-derived small molecule that selectively blocked the collagenase activity of cathepsin K and thus consequently bone degradation in an osteoporosis mouse model without affecting other known functions of the protease. The crucial difference might be that the red sage inhibitor did not block the cathepsin K-mediated degradation of TGF-ß1, a growth factor involved in fibrotic pathologies described in the clinical trials. TGF-ß1 degradation is blocked by these inhibitors and thus accumulates in tissues, causing fibrosis.
MedicalResearch.com: What should readers take away from your report?
Response: We demonstrated that it is possible to target the one specific activity of cathepsin K, its collagenase activity, which is relevant for osteoporosis. In doing so, we could demonstrate bone preservation in an osteoporosis mouse model without observing any side effects. This will provide a novel approach for the development of less side effect prone osteoporosis drugs.
MedicalResearch.com: What recommendations do you have for future research as a result of this study?
Response: Future research needs to address the on-target effects of drugs. Many pharmaceutical drug targets are multifunctional enzymes/receptors that have both disease-relevant and regulatory functions. The challenge will be to target only the disease-related activity of an enzyme and leave the other activities untouched. This will dramatically reduce side effects.
MedicalResearch.com: Is there anything else you would like to add?
Response: On-going research in our laboratory analyzes the mechanism of ectosteric inhibitors and compares their therapeutic outcome with those of active site-directed inhibitors in various disease models. Using cathepsin K as an example, we will demonstrate the feasibility and the advantages of this novel inhibitor concept. Our study was funded by the Canadian Institutes of Health Research. I want to thank in particular Dr. Preety Panwar who was and is the driving force in this project.
MedicalResearch.com: Thank you for your contribution to the MedicalResearch.com community.
Citation:
J Bone Miner Res. 2017 Jul 26. doi: 10.1002/jbmr.3227. [Epub ahead of print]
An Ectosteric Inhibitor of Cathepsin K Inhibits Bone Resorption in Ovariectomized Mice.
Panwar P1,2,3,4, Xue L1,2, Søe K3, Srivastava K1,2, Law S2,4, Delaisse JM3, Brömme D1,2,4.
Note: Content is Not intended as medical advice. Please consult your health care provider regarding your specific medical condition and questions.
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Last Updated on August 30, 2017 by Marie Benz MD FAAD