UBC Theses and Dissertations
Investigating the in vitro and in vivo anti-resorptive effects of herbal-and TCM-based extracts on Cathepsin K activity Zhou, Ru Jing
Osteoporosis is a chronic skeletal disease primarily affecting post-menopausal women and men over the age of 50. Current pharmacological interventions, such as bisphosphonates (BP) and denosumab, target the bone resorption process and have limitations in efficacy due to the disruption of important bone remodeling mechanisms and thus reducing bone formation and quality. Cathepsin K (CatK) is the major enzyme that is responsible for the breakdown of type I collagen in the bone matrix, therefore inhibitors of CatK have been a new approach to the treatment of osteoporosis without decreasing bone formation. Several active site CatK inhibitors such as odanacatib (ODN) have shown high efficacy in clinical trials, but were not approved due to risks of adverse effects. Adverse effects were postulated to be due to inhibition of CatK normal physiological as well as pathophysiological functions such as its part in the catabolism of essential growth hormones. Exosite inhibitors extracted from red sage plants, such as tanshinone IIA sulfonic sodium (T06) and dihydrotanshinone-1 (DHT-1) have so far shown a potent anti-resorptive effect while demonstrating an increased specificity in targeting the disease-related collagenase activity of CatK. These inhibitors are able to bind at a site on CatK to prevent collagenase activity while leaving other enzymatic activities unaltered. The major aim of my thesis will be to elucidate the in vitro and in vivo efficacy of herbal-based CatK inhibitors in the treatment of osteoporosis. The in vitro and in vivo efficacy of a pan-tanshinone-containing extracts of Salvia Milthorizoa (SM) , and a formulation used in Traditional Chinese medicine where SM is part of a multi-herbal combination (XLGB Pills), which will be compared against a standard-of-care bisphosphonate through the analysis of bone microstructural as well as CatK activity subsequent to these treatments.
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