Biomimetic Hyaluronic Acid-Based Brush Polymers Modulate Chondrocyte Homeostasis via ROS/Ca2+/TRPV4

摘要

Bionic mimics using natural cartilage matrix moleculescan modulatethe corresponding metabolic activity by improving the microenvironmentof chondrocytes. A bionic brush polymer, HA/PX, has been found toreverse the loss of cartilage extracellular matrix (ECM) and has promisingapplications in the clinical treatment of osteoarthritis (OA). However,the unknown bioremediation mechanism of HA/PX severely hinders itsclinical translation. In OA, the massive loss of the ECM may be attributedto a decrease in transient receptor potential vanilloid 4 (TRPV4)activity, which affects reactive oxygen species (ROS) clearance and[Ca2+]( i ) signaling, initiatingdownstream catabolic pathways. In this study, we investigated thebioremediation mechanism of HA/PX in a model of interleukin 1 & beta;(IL-1 & beta;)-induced inflammation. Through TRPV4, HA/PX reduced ROSaccumulation in chondrocytes and enhanced [Ca2+]( i ) signaling, reflecting a short-term protection capacityfor chondrocytes. In addition, HA/PX balanced the metabolic homeostasisof chondrocytes via TRPV4, including promoting the secretion of typeII collagen (Col-II) and aggrecan, the major components of the ECM,and reducing the expression of matrix metal-degrading enzyme (MMP-13),exerting long-term protective effects on chondrocytes. Molecular dynamics(MD) simulations showed that HA/PX could act as a TRPV4 activator.Our results suggest that HA/PX can regulate chondrocyte homeostasisvia ROS/Ca2+/TRPV4, thereby improving cartilage regeneration.Because the ECM is a prevalent feature of various cell types, HA/PXholds promising potential for improving regeneration and disease modificationfor not only cartilage-related healthcare but many other tissues anddiseases.

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