Modeling Osteocyte Network Formation: Healthy and Cancerous Environments.

Advanced cancers, such as prostate and breast cancers, commonly metastasize to bone. In the bone matrix, dendritic osteocytes form a spatial network allowing communication between osteocytes and the osteoblasts located on the bone surface. This communication network facilitates coordinated bone remodeling. In the presence of a cancerous microenvironment, the topology of this network changes. In those situations, osteocytes often appear to be either overdifferentiated (i.e., there are more dendrites than healthy bone) or underdeveloped (i.e., dendrites do not fully form). In addition to structural changes, histological sections from metastatic breast cancer xenografted mice show that number of osteocytes per unit area is different between healthy bone and cancerous bone. We present a stochastic agent-based model for bone formation incorporating osteoblasts and osteocytes that allows us to probe both network structure and density of osteocytes in bone. Our model both allows for the simulation of our spatial network model and analysis of mean-field equations in the form of integro-partial differential equations. We considered variations of our model to study specific physiological hypotheses related to osteoblast differentiation; for example predicting how changing biological parameters, such as rates of bone secretion, rates of cancer formation, and rates of osteoblast differentiation can allow for qualitatively different network topologies. We then used our model to explore how commonly applied therapies such as bisphosphonates (e.g., zoledronic acid) impact osteocyte network formation.