Background: Senile osteoporosis (SOP) is characterized by diminished bone mass and deteriorated bone microstructure. A key pathogenic factor of it is the impaired mechanosensing function of osteocytes, whose mechanism remains unclear. The mechano-response of osteocytes depends on the physical microenvironment of the lacunar-canalicular system (LCS). While advanced glycation end products (AGEs) accumulation impairs bone quality at meso-level, its correlation with the micro-level LCS physical microenvironment and osteocyte function remains unclear. This study investigated the association between AGE accumulation and the LCS physical microenvironment during aging, specifically focusing on its morphology and micromechanical properties. Furthermore, the expression of mechanosensing elements in osteocyte processes were evaluated within the context of these microenvironmental changes to explore their potential functional impact.
Methods: Sixteen female C57BL6J mice were divided into young (2-month-old, 2 M) and aged (18-month-old, 18 M) groups. Bone microstructure was evaluated by Micro-computed tomography (micro-CT); LCS/osteocyte morphology and pericanalicular elastic modulus were determined by Transmission electron microscopy (TEM) and Atomic force microscopy (AFM); bone pentosidine (PEN) and fluorescent AGEs were detected by High-performance liquid chromatography (HPLC) and fluorescence microscopy. Pericanalicular PEN and carboxymethyl-lysine (CML) was quantified by confocal Raman spectroscopy (CRS), and their correlation with indicators of LCS physical microenvironment was analyzed; osteocyte mechanosensing elements (integrin αVβ3, tethering elements (TEs)/Perlecan(PLN)) were assessed by immunofluorescence staining.
Results: The results showed that compared to the 2 M group, the 18 M group exhibited significantly higher AGEs at both meso- and micro-levels. This accumulation correlated with adverse physical changes in LCS including a smaller canalicular cross-sectional area and higher pericanalicular elastic modulus. Furthermore, the aged mice displayed a reduction in mechanosensing elements, indicated by significantly fewer TEs and lower PLN expression in osteocytes.
Conclusions: Our findings indicate that AGEs accumulate in the pericanalicular matrix with aging, which is accompanied with the alterations in canalicular physical properties, including the canalicular narrowing and pericanalicular matrix stiffening. This physical deterioration potentially contributes to the significant downregulation of key mechanosensing elements in osteocyte processes, via theoretically attenuating interstitial fluid flow and matrix strain. This study highlights a critical association between age-related AGE accumulation and the compromised mechanosensing environment for osteocytes, offering a novel perspective for understanding SOP mechanisms and exploring potential therapeutic interventions.
Keywords: Advanced glycation end products (AGEs); Mechanosensing elements; Osteocyte; Senile osteoporosis (SOP); lacuna-canalicular system (LCS).
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