An Agent-based Model for Evaluating Cellular Mechanisms of Bone Remodeling

In this thesis I present a mechanistic computational model of the cells and processes involved in bone remodeling. Despite decades of progress uncovering the mysteries of bone biology and developing a wide base of information on the cells and processes involved in bone maintenance, the most popular hypotheses for how bone cells interact and orchestrate controlled remodeling remain controversial and unverified. In order to leverage the primary literature towards testing the feasibility of two particular hypotheses, I created an agent-based model (ABM) structured on the known locations, properties, and behaviors of osteoclasts, osteocytes, and osteoblasts.

Bone’s ability to minimize mass without jeopardizing mechanical integrity can be explained by a disuse signaling threshold, but the mechanics and source of this signaling pathway are still largely a mystery. The preliminary model presented here simulates the hypothesis that a simple osteocyte-released and osteoclast-received signal could maintain trabecular width at the minimum required to support the applied load. Using a series of different initialization parameters, the initial simulation suggests that a mechanically stimulated osteocyte signal can dynamically maintain an optimized trabecular width.

The second iteration of the ABM incorporated known information on osteoblasts and simulated the hypothesis that osteoclasts could be temporally and spatially coupled to osteoclasts via a diffusible signaling molecule released from the bone matrix during osteoclastic resorption. This simulation shows that there exists a set of input parameters, within the range supported by literature, which will generate controlled remodeling. These results support the hypothesis that osteoblasts could be spatially coupled to osteoclasts by a released signal. However, the simulation raises some questions about this popular hypothesis’s ability to correctly account for the timing of osteoblast activation and migration towards the remodeling compartment.