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

Bionic mimics using natural cartilage matrix molecules can modulate the corresponding metabolic activity by improving the microenvironment of chondrocytes. A bionic brush polymer, HA/PX, has been found to reverse the loss of cartilage extracellular matrix (ECM) and has promising applications in the clinical treatment of osteoarthritis (OA). However, the unknown bioremediation mechanism of HA/PX severely hinders its clinical translation. In OA, the massive loss of the ECM may be attributed to a decrease in transient receptor potential vanilloid 4 (TRPV4) activity, which affects reactive oxygen species (ROS) clearance and [Ca²⁺] signaling, initiating downstream catabolic pathways. In this study, we investigated the bioremediation mechanism of HA/PX in a model of interleukin 1β (IL-1β)-induced inflammation. Through TRPV4, HA/PX reduced ROS accumulation in chondrocytes and enhanced [Ca²⁺] signaling, reflecting a short-term protection capacity for chondrocytes. In addition, HA/PX balanced the metabolic homeostasis of chondrocytes via TRPV4, including promoting the secretion of type II 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 homeostasis via ROS/Ca²⁺/TRPV4, thereby improving cartilage regeneration. Because the ECM is a prevalent feature of various cell types, HA/PX holds promising potential for improving regeneration and disease modification for not only cartilage-related healthcare but many other tissues and diseases.