Mathematical modelling of bone remodelling at the cellular level and the interaction between myeloma cells and the bone microenvironment

After an initial phase of growth and development, bone undergoes a continuous cycle of repair, renewal and optimization, by a process termed remodelling. Bone remodelling is the coordinated processes of resorption by osteoclasts and formation by osteoblasts, where old bone is replaced by new bone. Disorder of bone remodelling cycle can result in metabolic bone diseases, such as postmenopausal osteoporosis, hypothyroidism and primary hyperparathyroidism. Due to the large number of bone cell types, stages of differentiation, and the numerous growth factors and cell to cell interactions involved, our current understanding of bone remodelling and the coupling between osteoblasts and osteoclasts is still fragmentary. In the first part of this research, a novel predator-prey based mathematical model is developed to simulate bone remodelling cycles in trabecular bone at the basic multicelluar unit level, through integrating bone removal by osteoclasts and formation by osteoblasts. The model is able to replicate the curves of bone remodelling cycles obtained from standard bone histomorphometric analysis. The application of the model is firstly demonstrated by using experimental data recorded for normal (healthy) bone remodelling, to simulate the temporal variation in the number of osteoblasts and osteoclasts, and resultant effect on bone thickness. The reconstructed histomorphometric data and remodelling cycle characteristics compared well with the specified input data. Two sample pathological conditions, hypothyroidism and primary hyperparathyroidism, were then examined to demonstrate how the model could be applied more broadly. The model was validated by comparing model predictions (maximum populations of osteoclasts and osteoblasts) in the normal condition with experimental data. Further data is required to fully validate the model’s predictive capability. A second mathematical model is then developed to simulate how the interaction between multiple myeloma (MM) cells and the bone microenvironment leads to a ‘vicious cycle’ between tumour development and bone destruction. The model includes the roles of inhibited osteoblast activity and stimulated osteoclast activity, and is able to mimic the temporal variation of bone cell concentrations and resultant bone volume after invasion and then removal of the tumour cells. The model explains why MM-induced bone lesions rarely heal even after the complete removal of MM cells. The model’s predictions agree with published experimental and clinical observations. The model is also used to simulate therapies for MM-induced bone disease, including bisphosphonates, bortezomib and the inhibition of TGF-β. The simulation confirms that treatments with bisphosphonates and bortezomib can reduce the tumour burden and bone destruction, which is consistent with clinical observations. However, the inhibition of TGF-β does not appear to suppress bone destruction, although it does decrease the MM cell concentration

Mathematical modelling of bone remodelling at the cellular level and the interaction between myeloma cells and the bone microenvironment

After an initial phase of growth and development, bone undergoes a continuous cycle of repair, renewal and optimization, by a process termed remodelling. Bone remodelling is the coordinated processes of resorption by osteoclasts and formation by osteoblasts, where old bone is replaced by new bone. Disorder of bone remodelling cycle can result in metabolic bone diseases, such as postmenopausal osteoporosis, hypothyroidism and primary hyperparathyroidism. Due to the large number of bone cell types, stages of differentiation, and the numerous growth factors and cell to cell interactions involved, our current understanding of bone remodelling and the coupling between osteoblasts and osteoclasts is still fragmentary.In the first part of this research, a novel predator-prey based mathematical model is developed to simulate bone remodelling cycles in trabecular bone at the basic multicelluar unit level, through integrating bone removal by osteoclasts and formation by osteoblasts. The model is able to replicate the curves of bone remodelling cycles obtained from standard bone histomorphometric analysis. The application of the model is firstly demonstrated by using experimental data recorded for normal (healthy) bone remodelling, to simulate the temporal variation in the number of osteoblasts and osteoclasts, and resultant effect on bone thickness. The reconstructed histomorphometric data and remodelling cycle characteristics compared well with the specified input data. Two sample pathological conditions, hypothyroidism and primary hyperparathyroidism, were then examined to demonstrate how the model could be applied more broadly. The model was validated by comparing model predictions (maximum populations of osteoclasts and osteoblasts) in the normal condition with experimental data. Further data is required to fully validate the model’s predictive capability.A second mathematical model is then developed to simulate how the interaction between multiple myeloma (MM) cells and the bone microenvironment leads to a ‘vicious cycle’ between tumour development and bone destruction. The model includes the roles of inhibited osteoblast activity and stimulated osteoclast activity, and is able to mimic the temporal variation of bone cell concentrations and resultant bone volume after invasion and then removal of the tumour cells. The model explains why MM-induced bone lesions rarely heal even after the complete removal of MM cells. The model’s predictions agree with published experimental and clinical observations. The model is also used to simulate therapies for MM-induced bone disease, including bisphosphonates, bortezomib and the inhibition of TGF-β. The simulation confirms that treatments with bisphosphonates and bortezomib can reduce the tumour burden and bone destruction, which is consistent with clinical observations. However, the inhibition of TGF-β does not appear to suppress bone destruction, although it does decrease the MM cell concentration

DEVELOPMENT AND APPLICATION OF A MORPHOLOGICAL MODEL FOR TRABECULAR BONE

Ph.DDOCTOR OF PHILOSOPH

Mapping Trabecular Bone Fabric Tensor by in Vivo Magnetic Resonance Imaging

The mechanical competence of bone depends upon its quantity, structural arrangement, and chemical composition. Assessment of these factors is important for the evaluation of bone integrity, particularly as the skeleton remodels according to external (e.g. mechanical loading) and internal (e.g. hormonal changes) stimuli. Micro magnetic resonance imaging (µMRI) has emerged as a non-invasive and non-ionizing method well-suited for the repeated measurements necessary for monitoring changes in bone integrity. However, in vivo image-based directional dependence of trabecular bone (TB) has not been linked to mechanical competence or fracture risk despite the existence of convincing ex vivo evidence. The objective of this dissertation research was to develop a means of capturing the directional dependence of TB by assessing a fabric tensor on the basis of in vivo µMRI. To accomplish this objective, a novel approach for calculating the TB fabric tensor based on the spatial autocorrelation function was developed and evaluated in the presence of common limitations to in vivo µMRI. Comparisons were made to the standard technique of mean-intercept-length (MIL). Relative to MIL, ACF was identified as computationally faster by over an order of magnitude and more robust within the range of the resolutions and SNRs achievable in vivo. The potential for improved sensitivity afforded by isotropic resolution was also investigated in an improved µMR imaging protocol at 3T. Measures of reproducibility and reliability indicate the potential of images with isotropic resolution to provide enhanced sensitivity to orientation-dependent measures of TB, however overall reproducibility suffered from the sacrifice in SNR. Finally, the image-derived TB fabric tensor was validated through its relationship with TB mechanical competence in specimen and in vivo µMR images. The inclusion of trabecular bone fabric measures significantly improved the bone volume fraction-based prediction of elastic constants calculated by micro-finite element analysis. This research established a method for detecting TB fabric tensor in vivo and identified the directional dependence of TB as an important determinant of TB mechanical competence

Translational Cell & Animal Research in Space 1965-2011

Translational Cell and Animal Research (TCAR). For nearly 50 years, the NASA Space Biology Program has funded, and Ames Research Center (ARC) has managed, a robust program of fundamental research including studies using a wide range of animal cells, tissues and organisms. Much of this research was conducted on spacecraft in microgravity environments including diverse platforms such as: Gemini Spacecraft, US Biosatellites, Apollo Command Modules, Skylabs, Russian Biosatellites, NASA Space Shuttles, NASA/Mir, and most recently, the International Space Station (ISS). During the Space Shuttle Era (19812011), the science of space biology took an enormous step forward with 45 missions that afforded researchers with new opportunities to conduct systematic and complex experiments aimed at a deeper understanding of how life adapts to the space environment. Beginning in the 1990s, the products of these experiments, comprised of research summaries and rare, unused biospecimens, were collected and catalogued within the ARC Life Sciences Data Archiving Office, a branch of NASAs Life Sciences Data Archive (LSDA) managed from the NASA Johnson Spaceflight Center

Life Sciences Program Tasks and Bibliography for FY 1996

This document includes information on all peer reviewed projects funded by the Office of Life and Microgravity Sciences and Applications, Life Sciences Division during fiscal year 1996. This document will be published annually and made available to scientists in the space life sciences field both as a hard copy and as an interactive Internet web page