Growing evidence shows that osteocytes, the most abundant bone cells, serve as the primary sensory cells that detect external mechanical forces [1], enabling the bone to adapt its mass and structure to meet its environmental requirements and to fulfill its weight bearing functions [2]. Although the cellular and molecular mechanisms of such adaptation phenomena are not fully understood, recent experiments and theoretical models suggest that the pericellular matrix (PCM) filling the tiny gap between the cell membrane and the canalicular matrix wall plays a critical role in the osteocytes’ outside-in signaling process [1]. Weinbaum first hypothesized that a proteoglycan-like fiber matrix, similar to the endothelial glycocalyx, must exist within the PCM to account for the surprisingly long relaxation times of the strain-generated potentials measured in bone [3]. Such a filling matrix was predicted to impose hydraulic resistance, impede fluid pressure relaxation and reduce fluid flow in the tiny lacunar-canalicular pore system in bone, thus protecting the cell membranes from being ruptured under shear. Later electronic microscopic studies confirmed the existence and the proteoglycan nature of the PCM [4]. Previous models using idealized PCM ultrastructure suggested that the hydrodynamic interactions between the PCM and fluid could determine the magnitude of drag forces that deform cytoskeleton via tethered transmembrane components or the focal contacts containing integrins [5,6]. In both scenarios, the PCM is the key to force transmission and strain signal amplification, and responsible for downstream mechanotransduction. In addition, once the mechanically excited osteocytes affect the release of molecular signals such as ATP, NO, PGE2, OPG, RANKL, and sclerostin [2], the PCM, as a molecular sieve and temporary storage, may influence the transport and availability of these bioactive molecules [7]. Therefore, the structural and sieving properties of PCM are important in regulating bone’s mechanotransduction and adaptation. However, due to the small dimensions of the PCM (∼100nm thick) and the difficulty in preserving the PCM in situ, its detailed structure and properties have remained elusive [4]. The objective of this study was to elucidate the sieving property of the PCM in mechanically loaded bone with an innovative imaging approach and to further deduce plausible PCM structures using mathematical modeling.

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