Glycosaminoglycans Differentially Modulate Meniscus Pericellular Matrix Micromechanics and Mechanosensing

Abstract

In the meniscus, cells reside within a specialized pericellular matrix (PCM) microniche that exhibits distinct molecular and structural features compared to the surrounding fibrous extracellular matrix (ECM). The PCM is enriched in negatively charged sulfated glycosaminoglycans (sGAGs), primarily contributed by localized proteoglycans such as aggrecan. Using the murine meniscus as the model, this study delineates the specific contributions of sGAGs to the elastic and viscoelastic micromechanics of the PCM and explores their influence on resident cell mechanosensing. Enzymatic removal of sGAGs markedly decreases the PCM micromodulus and alters its viscoelastic properties, including faster relaxation time constants. Finite element modeling suggests that the localized fixed charges and mechanical buffering provided by sGAGs in the PCM serve as a protective mechanism for resident cells under tensile loading, the predominant loading mode of the meniscus outer zone in vivo. Nevertheless, despite these pronounced contributions to PCM micromechanics, sGAG depletion induces a modest reduction in intracellular calcium signaling ex vivo under hypertonic, but not isotonic or hypotonic, conditions. Collectively, these findings establish sGAGs as critical regulators of fibrocartilage PCM integrity and highlight their differential roles in local PCM micromechanics versus cell mechanosensing.