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

Abstract

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 [Ca 2+ ] i 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 [Ca 2+ ] i 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/Ca 2+ /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 cartilagerelated healthcare but many other tissues and diseases.

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“…In this context, Ren et al amalgamated two distinct polymer brushes (HA/PA and HA/PM), building upon previous research, to elucidate the antiinflammatory mechanisms and efficacies of HA/PX composite polymer brushes (Figure 5a). [150] Empirical evidence from their study indicated that HA/PX exhibits a potent capacity to scavenge free radicals in vitro, mitigate the intracellular ROS accumulation in inflammatory milieus, and thus conferred protection to chondrocytes. Furthermore, HA/PX demonstrated a restorative effect on impaired [Ca 2+ ] signaling within inflamed chondrocytes.…”

“…The process commenced with the extraction and in vitro expansion of chondrocytes, followed by the induction of apoptosis. Subsequently, the apoptotic cell [150] Copyright 2023, ACS Publications. b) Immune cell mobilized hydrogel microspheres treat osteoarthritis through anti inflammation.…”

“…a) Chondrocytes secrete matrix proteins after HA/PX treatment, reversing the massive loss of ECM components in the inflammatory environment. Reproduced with permission [150]. Copyright 2023, ACS Publications.…”