Mathematical modelling of bone remodelling in mechanical, electro-magnetic fields at the cellular level
Creators: name: Wang, Yanan
Publisher: name: The Australian National University
Year: 2010
Subjects: subject: QP88.2.W36 2010
subject: Bone remodeling Mathematical models
subject: Bone regeneration Physiology

description: The skeleton is a metabolically active organ that undergoes continuous remodelling throughout life. At the cellular level, bone remodelling is an organised process whereby osteoclasts remove old bone and osteoblasts replace them with newly formed bone. The osteoclasts and osteoblasts work together in a coupled manner within a so-called 'basic multicellular unit' (BMU). Bone remodelling helps to repair microdamages in bone matrix, preventing the accumulation of old bone. It also plays an important role in maintaining plasma calcium homeostasis. The regulation of bone remodelling is both systemic and local. The most important systemic regulator is parathyroid hormone (PTH), which has been used as a therapy to treat osteoporosis in clinics; however, the underlying mechanism by which PTH is regulated is still not clear. As far as local regulation of bone remodelling is concerned, the discovery of the RANKIRANKL/OPG pathway is significant to the understanding of the interaction between osteoclastic cells and osteoblastic cells in BMU. A large number of therapeutic drugs and other stimuli have been found to apply their effects via RANKIRANKL/OPG. Mechanical stimulus has significant influence on bone remodelling. Disuse or lack of loading causes bone remodelling with bone resorption dominating bone formation and thus a loss of bone mass or density. Conversely, overuse or increased loading causes bone mass or density to increase. Additionally, loadings with different characteristics such as frequency, number of loading cycles in a session and rest time between loading bouts affects bone remodelling differently. However, the underlying mechanisms are not fully understood despite a great deal of experimental work in this field. Pulsed electro-magnetic fields (PEMF) devices have been widely used in clinics to treat bone fracture non-union and shorten the recovery period of fracture. Despite the clinical success, it is still not clear how PEMF stimulus interacts with cells, factors or molecules that are involved in bone remodelling. This thesis will use a computational system biology approach to address the issues proposed above. Computational system biology is a systems biology approach that integrates experimental and computational research in order to understand complex biological systems such as bone remodelling. Based on the latest experimental results and mathematical advances, a mathematical model of bone remodelling at the cellular level is developed with PTH included. Building on this platform model, mechanical stimulus and PEMF are taken into account. Thus, their effects on bone remodelling and the underlying control mechanisms at the cellular level are investigated. The work in the thesis will further current understanding of bone remodelling at the cellular level. The quantitative analysis using our model will help pharmacological and non-pharmacological therapies developments, which eventually benefit patients who suffer from bone loss diseases such as osteoporosis.