Exploring complex cellular interactions: mathematical modeling and experimental studies of bone turnover

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RATIONALE: Bone mechanical properties depend on the process of bone remodeling, which involves resorption by osteoclasts, followed by formation of new bone by osteoblasts organized in Bone Multicellular Units (BMUs). Bone remodeling is regulated by local and systemic biochemical factors. Mechanical forces also regulate the activity of the bone cells and guide BMU movement. The responses of bone cells to mechanical forces involve deformation-induced changes within bone cells, and alterations in the production of soluble factors, such as ATP, that regulate cell-cell communications. The goal of my program is to understand how mechanical forces regulate bone cells immediate activity and their ability to perform physiological function, and how physical environment of individual cells is integrated in the performance of bone as an organ.****CURRENT OBJECTIVES:****1. To examine how mechanical force information is integrated by an individual bone cell.****2. To investigate short-range cell-cell communications induced by mechanical forces in bone cells.****3. To incorporate the description of the mechanosensitivity of individual cells into the tissue scale mathematical model of bone turnover.****METHODOLOGY: We established that local osteoblast membrane deformation leads to calcium channels opening and elevation of cytosolic calcium, which exhibits threshold properties when cell micro-injury is induced. Mathematical model combining the calcium channel dynamics with intracellular calcium handling will be used to study the threshold formation. Model predictions will be tested using atomic force and fluorescence microscopy of individual osteoblasts. Mechanical stimulation of a single cell was also found to lead to the release of soluble mediator (identified as ATP), which induced delayed secondary responses in neighboring non-connected cells. Since the response changed with the distance from the stimulated cell, we hypothesize that extracellular degradation of ATP to ADP leads to activation of distinct nucleotide receptors at different distance from the stimulated cell. Mathematical model accounting for diffusion and degradation of ATP released from the primary cell will be used to predict ATP/ADP levels at different distance from the stimulated cell. We will examine the roles of individual nucleotide receptors using RNA interference. We have previously developed a partial differential equation model describing the biochemically guided BMU movement through the bone tissue. To account for steering of bone turnover by mechanical factors, we will incorporate the models of mechanosensitivity of osteoblasts and osteoclasts into the BMU model.****IMPACT: This work will contribute to a better understanding of the principles of spatial and temporal regulation of systems involving complex biochemical and mechanical interactions among different cell types, a key question in developmental biology.***