The Pro-apoptotic Mechanism and Anti-apoptotic Pathways of Osteoclasts and Osteoclast Precursors

Abstract

Osteoporosis can cause severe disability It may increase the risk of death especially when hip fractures occur The incidence of osteoporosis and hip fracture is high in Taiwan (the highest in Asia) However the treatment results for osteoporosis are dismal Osteoporosis is caused by the imbalance of osteoblasts and osteoclasts The bone formation of functioning osteoblasts is suppressed whereas osteoclasts are over activated for bone resorption Understanding the mechanism of osteoclast apoptosis and the resistance pathways of treatment may help identify new therapeutic targets The purpose of this study was to investigate the mechanism of cell apoptosis and the survival of osteoclasts following osteoporosis treatment The three specific aims are as follows: Specific Aim 1: To understand the mechanism of cell apoptosis in osteoclast precursors and osteoclasts Specific Aim 2: To understand the mechanism of cell survival in osteoclast precursors and osteoclasts after treatment for osteoporosis Specific Aim 3: To test the therapeutic effect of enhancing the apoptotic pathway or inhibiting the cell survival pathway The results showed that Zoledronic acid-induced apoptosis was mediated by the activation of reactive oxygen species and GSK-3β followed by Mcl-1 downregulation and mitochondrial damage resulting in apoptosis In some cells the p38 MAPK-mediated pathway was activated to enhance cell survival This effect was mediated by GSK-3β-β-catenin-Bcl-xL signaling Furthermore we found that co-treatment with ZA and a p38 inhibitor might enhance the treatment in an osteoporosis animal model We identified the intracellular pro-apoptotic and anti-apoptotic pathways of osteoclast precursors and developed a new treatment strategy The results contribute to the knowledge of the pathophysiology of osteoporosis and have clinical relevance

Date of Award	2016 Aug 22
Original language	English
Supervisor	Fong-chin Su (Supervisor)