Exploring complex cellular interactions: mathematical modeling of bone mineralization, turnover, and mechanobiology

点击翻译按钮获取中文摘要

BACKGROUND: Bone plays distinct roles in locomotion and calcium homeostasis. Bone mechanical properties are determined by its composition and structure. Bone tissue composition is controlled by osteoblasts, which produce a collagenous matrix that upon maturation nucleates precipitation of hydroxyapatite. Bone structure depends on bone (re)modeling - a coordinated process of tissue shaping that includes resorption by osteoclasts, formation by osteoblasts and over-reaching regulation by bone-resident osteocytes, cells especially important for mechanoadaptation. During the previous funding cycles, we developed mathematical models describing features of bone mineralization, spatiotemporal progression of bone remodeling, and mechanoregulation of osteoblasts and osteocytes. My next focus will be to understand the interactions and relative contributions of biological and mechanical factors in determining the outcome of bone turnover. OVERALL OBJECTIVE: To develop conceptual models of cellular control of bone (re)modeling that integrates bone responsiveness to the local mechanical environment with it diverse endocrine roles. RESEARCH PLAN: Aim 1: To examine bone mechanoadaptation I plan to develop theoretical models that include the short-term responses of individual cells and the long-term mechanoadaptation outcomes. We recently identified cell injury as critical in bone cell mechano-response, and developed a model of fast propagation of mechano-biological signal through bone tissue. To examine coordination between acute responses and long-term mechanoadaptation, we will incorporate this model with the previously developed model of bone cell interactions during bone remodeling. Aim 2: To understand the endocrine function of bone, I will study the relationships between the need in calcium and phosphate for bone mineralization and the role of bone in providing these minerals for the whole body calcium and phosphorus homeostasis. Our model of biological regulation of mineralization will be expanded to include physical chemistry of calcium/phosphate precipitation, and combined with models of hormonal regulation of calcium/phosphorus homeostasis. Aim 3: To examine how hormonal and mechanical inputs are integrated by bone cells, I plan to combine the models developed in aims 1 and 2 to identify the parameters that determine which functions will be prioritized by the cells receiving the signal. Aim 4. To improve the use of meta-analytic approaches to obtain reliable estimates of model parameters, I plan to develop theoretical foundation for use of specific meta-analytic schemes for different types of experimental data, and practical approaches to facilitate literature screening, data extraction, management, and analysis. SIGNIFICANCE: These studies will improve our understanding of principles underlying endocrine regulation of homeostasis, and provide new insights into the mechanisms that control architecture and strength of the vertebrate skeleton.