Fluid flow induced calcium response in osteoblasts: Mathematical modeling

Fluid flow in the bone lacuno-canalicular network can induce dynamic fluctuation of intracellular calcium concentration ([Ca2+]i) in osteoblasts, which plays an important role in bone remodeling. There has been limited progress in the mathematical modeling of this process probably due to its complexity, which is controlled by various factors such as Ca2+ channels and extracellular messengers. In this study we developed a mathematical model to describe [Ca2+]i response induced by fluid shear stress (SS) by integrating the major factors involved and analyzed the effects of different experimental setups (e.g. [Ca2+]i baseline, pretreatment with ATP). In this model we considered the ATP release process and the activities of multiple ion channels and purinergic receptors. The model was further verified quantitatively by comparing the simulation results with experimental data reported in literature. The results showed that: (i) extracellular ATP concentration has more significant effect on [Ca2+]i baseline (73% increase in [Ca2+]i with extracellular ATP concentration varying between 0 and 10 μM), as compared to that induced by SS (25% variation in [Ca2+]i with SS varying from 0 to 3.5 Pa); (ii) Pretreatment with ATP-medium results in different [Ca2+]i response as compared to the control group (ATP-free medium) under SS; (iii) Relative [Ca2+]i fluctuation over baseline is more reliable to show the [Ca2+]i response process than the absolute [Ca2+]i response peak. The developed model may improve the experimental design and facilitate our understanding of the mechanotransduction process in osteoblasts.