Functionalized Nanohydrogels decrease Inflammatory and Cartilage Degradation Biomarkers in an organoid model of horse cartilage tissue
Résumé
Osteoarthritis (OA), a common degenerative disease characterized in humans by debil- itating chronic pain and inflammation, is expected to become the fourth most important cause of disability worldwide by 2020. Horse has been considered and proved to be as one of the most relevant patient animal model to study OA based on the cellularity, structural, biochemical and mechanical properties of cartilage, but also on its ageing evolution. OA is responsible for 60% of lameness in horses and may lead to abrupt ends of racehorse’s career. No curative treatment is available and symptomatic treatments commonly used suffer from a limited efficiency and frequently adverse effects.The aim of this project is to develop a nanomedicine therapeutic approach based on func- tionalized hydrogels that could improve mechanical functions, protect the cartilage against inflammation and degradation processes, and reduce pain.Several formulations and concentrations of hydrogels were studied in vitro to evaluate their biocompatibility and phenotypic effects on equine articular chondrocytes (eAC). Dedifferen- tiated eAC were cultured in vitro as organoids in type I/III collagens sponges under hypoxia for 7 days, and interleukin-1bˆeta (IL-1β) was added into the media to mimic an inflammatory environment.First, the hydrogels formulations did not have cytotoxic effects and did not alter the prolif- eration and the viability of chondrocytes. Then, the expression of hyaline cartilage markers was downregulated by IL-1β which concomitantly induced a strong induction of inflamma- tory and catabolic markers. Interestingly, the combination of two formulations of hydrogels decreased the expression of mRNA encoding several degradation markers, such as some metalloproteinases (Mmp1, Mmp3 and Mmp13), agrecanase (Adamts5) and inflammatory markers (Ptgs2 and Inos). Finally, this combination reduced the expression of type I colla- gen protein in our cartilaginous organoids.The biocompatibility and effectiveness of these hydrogels’ formulations on inflammation and degradation allow considering in vivo study in horses first, for tolerance assessment and thereafter in horses that spontaneously suffered from osteoarthritis. These results showed that functionalized hydrogels could be an innovative therapeutic strategy in the treatment of OA.