Bone refilling in cortical basic multicellular units: insights into tetracycline double labelling from a computational model

Abstract

Bone remodelling is carried out by 'bone multicellular units' ([Formula: see text]s) in which active osteoclasts and active osteoblasts are spatially and temporally coupled. The refilling of new bone by osteoblasts towards the back of the [Formula: see text] occurs at a rate that depends both on the number of osteoblasts and on their secretory activity. In cortical bone, a linear phenomenological relationship between matrix apposition rate and [Formula: see text] cavity radius is found experimentally. How this relationship emerges from the combination of complex, nonlinear regulations of osteoblast number and secretory activity is unknown. Here, we extend our previous mathematical model of cell development within a single cortical [Formula: see text] to investigate how osteoblast number and osteoblast secretory activity vary along the [Formula: see text]'s closing cone. The mathematical model is based on biochemical coupling between osteoclasts and osteoblasts of various maturity and includes the differentiation of osteoblasts into osteocytes and bone lining cells, as well as the influence of [Formula: see text] cavity shrinkage on osteoblast development and activity. Matrix apposition rates predicted by the model are compared with data from tetracycline double labelling experiments. We find that the linear phenomenological relationship observed in these experiments between matrix apposition rate and [Formula: see text] cavity radius holds for most of the refilling phase simulated by our model, but not near the start and end of refilling. This suggests that at a particular bone site undergoing remodelling, bone formation starts and ends rapidly, supporting the hypothesis that osteoblasts behave synchronously. Our model also suggests that part of the observed cross-sectional variability in tetracycline data may be due to different bone sites being refilled by [Formula: see text]s at different stages of their lifetime. The different stages of a [Formula: see text]'s lifetime (such as initiation stage, progression stage, and termination stage) depend on whether the cell populations within the [Formula: see text] are still developing or have reached a quasi-steady state whilst travelling through bone. We find that due to their longer lifespan, active osteoblasts reach a quasi-steady distribution more slowly than active osteoclasts. We suggest that this fact may locally enlarge the Haversian canal diameter (due to a local lack of osteoblasts compared to osteoclasts) near the [Formula: see text]'s point of origin.