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Towards a cell-based mechanostat theory of bone: the need to account for osteocyte desensitisation and osteocyte replacement

Bone's mechanostat theory describes the adaptation of bone tissues to their mechanical environment. Many experiments have investigated and observed such structural adaptation. However, there is still much uncertainty about how to define the reference mechanical state at which bone structure is adapted and stable. Clinical and experimental observations show that this reference state varies both in space and in time, over a wide range of timescales. We propose an osteocyte-based mechanostat theory that links various timescales of structural adaptation with various dynamic features of the osteocyte network in bone. This theory assumes that osteocytes are formed adapted to their current local mechanical environment through modulation of morphological and genotypic osteocyte properties involved in mechanical sensitivity. We distinguish two main types of physiological responses by which osteocytes subsequently modify the reference mechanical state. One is the replacement of osteocytes during bone remodelling, which occurs over the long timescales of bone turnover. The other is cell desensitisation responses, which occur more rapidly and reversibly during an osteocyte's lifetime. The novelty of this theory is to propose that long-lasting morphological and genotypic osteocyte properties provide a material basis for a long-term mechanical memory of bone that is gradually reset by bone remodelling. We test this theory by simulating long-term mechanical disuse (modelling spinal cord injury), and short-term mechanical loadings (modelling daily exercises) with a mathematical model. The consideration of osteocyte desensitisation and of osteocyte replacement by remodelling is able to capture the different phenomena and timescales observed during the mechanical adaptation of bone tissues, lending support to this theory.