Spatio-temporal simulations of bone remodelling using a bone cell population model based on cell availability

Here we developed a spatio-temporal bone remodeling model to simulate the action of Basic Multicelluar Units (BMUs). This model is based on two major extensions of a temporal-only bone cell population model (BCPM). First, the differentiation into mature resorbing osteoclasts and mature forming osteoblasts from their respective precursor cells was modelled as an intermittent process based on precursor cells availability. Second, the interaction between neighbouring BMUs was considered based on a "metabolic cost" argument which warrants that no new BMU will be activated in the neighbourhood of an existing BMU. With the proposed model we have simulated the phases of the remodelling process obtaining average periods similar to those found in the literature: resorption ( $\sim 22$ days)-reversal (∼8 days)-formation (∼65 days)-quiescence (560-600 days) and an average BMU activation frequency of ∼1.6 BMUs/year/mm³. We further show here that the resorption and formation phases of the BMU become coordinated only by the presence of TGF-β (transforming growth factor β), i.e., a major coupling factor stored in the bone matrix. TGF-β is released through resorption so upregulating osteoclast apoptosis and accumulation of osteoblast precursors, i.e., facilitating the transition from the resorption to the formation phase at a given remodelling site. Finally, we demonstrate that this model can explain targeted bone remodelling as the BMUs are steered towards damaged bone areas in order to commence bone matrix repair.