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

背景：骨在运动和钙稳态中起着独特的作用。骨的力学性能是由其组成和结构决定的。骨组织组成由成骨细胞控制，成骨细胞产生胶原基质，成熟后形成羟基磷灰石沉淀。骨结构依赖于骨（再）建模——一个组织成形的协调过程，包括破骨细胞的吸收、成骨细胞的形成和骨驻留骨细胞的过度调节，骨驻留骨细胞对机械适应尤为重要。在之前的资助周期中，我们开发了描述骨矿化特征的数学模型，骨重塑的时空进展以及成骨细胞和骨细胞的机械调节。我的下一个重点将是了解生物和机械因素在决定骨转换结果中的相互作用和相对贡献。总体目标：建立骨（再）建模的细胞控制概念模型，将骨对局部机械环境的反应性与不同的内分泌作用结合起来。研究计划：目标1：为了研究骨机械适应，我计划建立包括单个细胞的短期反应和长期机械适应结果的理论模型。我们最近发现细胞损伤是骨细胞机械反应的关键，并建立了一个通过骨组织快速传播机械生物信号的模型。为了检查急性反应和长期机械适应之间的协调，我们将把这个模型与先前开发的骨重塑过程中骨细胞相互作用的模型结合起来。目的2：为了了解骨的内分泌功能，我将研究骨矿化对钙和磷酸盐的需求与骨在为全身钙和磷稳态提供这些矿物质中的作用之间的关系。我们的矿化生物调节模型将扩展到包括钙/磷酸盐沉淀的物理化学，并结合钙/磷稳态的激素调节模型。目标3：为了检查骨细胞如何整合激素和机械输入，我计划将目标1和目标2中开发的模型结合起来，以确定哪些功能将被接收信号的细胞优先考虑的参数。目标4。为了提高meta分析方法的使用，以获得可靠的模型参数估计，我计划为不同类型的实验数据使用特定的meta分析方案提供理论基础，并为文献筛选、数据提取、管理和分析提供实用方法。意义：这些研究将提高我们对体内平衡的内分泌调节原理的理解，并为控制脊椎动物骨骼结构和强度的机制提供新的见解。

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.