An agent based model for real-time signaling induced in osteocytic networks by mechanical stimuli

We recently observed that insertion of unloaded rest between each load cycle substantially enhanced bone formation induced by mild loading regimens. To begin to explore this result, we have developed an agent based model for real-time signaling induced when osteocytic networks are challenged by mechanical stimuli. In the model, activity induced in individual osteocytes were governed by the following cellular functions: (1) threshold levels of tissue strain magnitudes were required to initiate and maximally activate cells, (2) cell activity beyond thresholds were propagated within localized neighborhoods and influenced recipient cell activity, (3) cellular activity was modulated by 'molecular' stores and the rates at which stores were replenished when cells were quiescent. Using this model, the real-time response of osteocyte networks was determined as the average of individual cell activity. While not explicitly embedded within the model, interactions between cellular functions served as positive, negative, and end-point feedback mechanisms and resulted in unique real-time network responses to distinct mechanical stimuli. Specifically, the real-time network response to cyclic stimuli consisted of a large magnitude transient followed by low-level steady state fluctuations, while rest-inserted stimuli induced multiple secondary transients. Analysis of interaction patterns suggested that rest-inserted stimuli induced this enhanced and sustained signaling within osteocytic networks by enabling cell recovery of expended molecular stores and by efficiently utilizing properties inherent to cell-cell communication in bone. Importantly, this emergence based approach suggested mechanisms potentially underlying the benefit of rest-inserted stimuli and provides a unique framework for a broader exploration of mechanotransduction function within bone.