The novel hyaluronic acid granular hydrogel attenuates osteoarthritis progression by inhibiting the TLR‐2/NF‐κB signaling pathway through suppressing cellular senescence

Abstract

In patients with mild osteoarthritis (OA), two to four monthly injections are required for 6 months due to the degradation of hyaluronic acid (HA) by peroxidative cleavage and hyaluronidase. However, frequent injections may lead to local infection and also cause inconvenience to patients during the COVID‐19 pandemic. Herein, we developed a novel HA granular hydrogel (n‐HA) with improved degradation resistance. The chemical structure, injectable capability, morphology, rheological properties, biodegradability, and cytocompatibility of the n‐HA were investigated. In addition, the effects of the n‐HA on the senescence‐associated inflammatory responses were studied via flow cytometry, cytochemical staining, Real time quantitative polymerase chain reaction (RT‐qPCR), and western blot analysis. Importantly, the treatment outcome of the n‐HA with one single injection relative to the commercial HA product with four consecutive injections within one treatment course in an OA mouse model underwent anterior cruciate ligament transection (ACLT) was systematically evaluated. Our developed n‐HA exhibited a perfect unification of high crosslink density, good injectability, excellent resistance to enzymatic hydrolysis, satisfactory biocompatibility, and anti‐inflammatory responses through a series of in vitro studies. Compared to the commercial HA product with four consecutive injections, a single injection of n‐HA contributed to equivalent treatment outcomes in an OA mouse model in terms of histological analysis, radiographic, immunohistological, and molecular analysis results. Furthermore, the amelioration effect of the n‐HA on OA development was partially ascribed to the attenuation of chondrocyte senescence, thereby leading to inhibition of TLR‐2 expression and then blockade of NF‐κB activation. Collectively, the n‐HA may be a promising therapeutic alternative to current commercial HA products for OA treatment.

A Novel Role for Protein Tyrosine Phosphatase 1B in Alleviating Chondrocyte Senescence

“…The destruction of periarticular bone and cartilage is a significant contributing element to OA, a prevalent chronic joint degenerative disease . It has been demonstrated that cellular senescence happens in OA chondrocytes and accelerates the development of OA. , Therefore, it is crucial to understand how cellular senescence-related genes in chondrocytes work in order to treat OA. Candidate biomarkers associated with cellular senescence can be found using bioinformatics techniques.…”

Enhanced Surface Immunomodification of Engineered Hydrogel Materials through Chondrocyte Modulation for the Treatment of Osteoarthritis

“…Inhibiting the NF-κB pathway may alleviate OA [125]. Zhang et al attenuated OA progression by inhibiting the NF-κB pathway and suppressing chondrocyte senescence [126]. The aberrant activation of pathways, like JAK-STAT, MAPK, and Wnt, plays key roles in cell functions.…”

Regulation of cellular senescence by innate immunity

“…It is reported that TLR2 can induce senescence in intervertebral disc cells, and o-vanillin may be a suitable drug for these patients (Mannarino et al 2021 ). Similarly, another study gives the novel hyaluronic acid granular hydrogel as a new strategy for osteoarthritis progression via suppressing TLR2-mediated cellular senescence (Zhang et al 2023 ). Furthermore, TLR3 causes senescence in patients infected with COVID-19 and tremendously increases SASP production (Tripathi et al 2021 ).…”