Peptides from Antarctic Krill (Euphausia superba) Improve Osteoarthritis via Inhibiting HIF-2α-Mediated Death Receptor Apoptosis and Metabolism Regulation in Osteoarthritic Mice

Osteoarthritis (OA) is a prevalent debilitating disease which is predominantly characterized by cartilage degeneration. In the current study, destabilization of the medial meniscus (DMM) mouse model was used to investigate the effects of Antarctic krill peptides (AKP) on cartilage protection. As observed, AKP clearly ameliorate cartilage degeneration as evidenced by increased cartilage thickness and cartilage area and decreased histological Osteoarthritis Research Society International (OARSI) scores. Toluidine blue staining showed that AKO remarkably inhibited the loss of cartilage matrix in mice with OA. Hypoxia-inducible factor-2 alpha (HIF-2 alpha) has a key role in catabolic regulation and inflammation cascades which are the main causes of OA. AKP can down-regulate the expression of HIF-2 alpha and its downstream genes such as MMP-13, Adamts-S, IL-1 beta, iNOS, CXCL-1, and NOS2. Consistent with this, anabolic genes such as Acan and Col2 alpha 1 were restored after treatment with AKP. Chondrocyte apoptosis and the reduction in cartilage cell viability are also involved in the process of OA. The HIF-2 alpha-mediated death receptor apoptosis signaling pathway has been involved in the regulation of chondrocyte apoptosis. AKP can reduce the expressions of key pro-apoptosis genes in Fas-FasL and DR3-DR3L signaling pathways such as Fas, FasL, FADD, caspase8, caspase3, DR3, DR3L, RIP, and NF-kappa B. In addition, expressions of antiapoptosis genes such as c-AIP and c-FLIP were increased significantly. These findings indicate that AKP can be used as a new functional factor in the development of functional foods and chondroprotective drugs.