NOTCH-1 signalling and other molecular mechanisms in osteoarthritis: potential therapeutic role of olive-derived polyphenols

Abstract

Osteoarthritis (OA) is the most common joint disease and the primary cause of disability in the elderly. Chondrocytes, the only cell type in articular cartilage, are primarily involved in the progression of the disease. The molecular mechanisms underlying OA modifications are not entirely known. Current research in the field is focused on finding new targets and novel therapeutic approaches. Among these, nutraceuticals (including food-derived bioactive compounds) present an interesting option. Our study investigated the molecular mechanisms involved in the onset and progression of OA and, in particular, the role of NOTCH-1 signalling, a novel target of interest in the disease. NOTCH-1 is a major regulator of chondrocyte homeostasis in mature cartilage, but it is deregulated in OA therefore suggesting a potential role in the pathogenesis. We used primary chondrocytes derived from patients with OA undergoing total knee arthroplasty and C28/I2 cells, a human chondrocyte cell line. Our results indicate that this signalling pathway exerts a pivotal role in the progression of OA and especially in chondrocyte differentiation and matrix remodelling by the regulation of key pathways in OA, such as MMP-13, RUNX-2, VEGFA, NFKB1 and its regulator IKKα. NOTCH-1 silencing also prevented cartilage calcification and reduced cell death. Furthermore, we investigated the potential chondroprotective role of two olive-derived nutraceuticals, oleuropein (OE) and hydroxytyrosol (HT), in vitro. Our data showed an antioxidant effect of both compounds against LPS-induced ROS production in C28/I2 cells. In addition to that, OE and HT were effective in decreasing the expression of inflammation markers, as well as of NOTCH-1 and its downstream targets. In conclusion, our research proved that NOTCH-1 signalling pathway is a potential target of OA. Furthermore, olive-derived polyphenols are able to modulate this pathway suggesting a promising strategy in OA management

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