Senolytic activity of small molecular polyphenols from olive restores chondrocyte redifferentiation and promotes a pro-regenerative environment in osteoarthritis

Abstract

Articular cartilage and synovial tissue from patients with osteoarthritis (OA) show an overactivity of connexin43 (Cx43) and accumulation of senescent cells associated with disrupted tissue regeneration and disease progression. The aim of this study was to determine the effect of oleuropein on Cx43 and cellular senescence for tissue engineering and regenerative medicine strategies for OA treatment. Oleuropein regulates Cx43 promoter activity and enhances the propensity of hMSCs to differentiate into chondrocytes and bone cells, reducing adipogenesis. This small molecule reduce Cx43 levels and decrease Twist-1 activity in osteoarthritic chondrocytes (OACs), leading to redifferentiation, restoring the synthesis of cartilage ECM components (Col2A1 and proteoglycans), and reducing the inflammatory and catabolic factors mediated by NF-kB (IL-1ß, IL-6, COX-2 and MMP-3), in addition to lowering cellular senescence in OACs, synovial and bone cells. Our in vitro results demonstrate the use of olive-derived polyphenols, such as oleuropein, as potentially effective therapeutic agents to improve chondrogenesis of hMSCs, to induce chondrocyte re-differentiation in OACs and clearing out senescent cells in joint tissues in order to prevent or stop the progression of the disease.

Senolytic Peptide FOXO4-DRI Selectively Removes Senescent Cells From in vitro Expanded Human Chondrocytes

“…In the future, we will test more senolytics with different doses. Recently, oleuropein, a polyphenol, was shown to have the senolytic potential in OA chondrocytes ( Varela-Eirín et al, 2020 ). Whether it is able to selectively remove senescent chondrocytes created by the in vitro expansion requires additional study.…”

Role of Physical Exercise and Nutraceuticals in Modulating Molecular Pathways of Osteoarthritis

“…Olive oil polyphenols (OOPs), as oleocanthal (OC), oleuropein (OP), tyrosol (TY), and hydroxytyrosol (HT), could modulate inflammatory and degenerative OA molecular patterns. OOPs inhibit pro-inflammatory genes expression through the suppression of NF-κB and MAPK activation, while enhancing Nrf-2 signaling [ 125 , 126 , 127 , 128 ].…”

The Impact of Polyphenols-Based Diet on the Inflammatory Profile in COVID-19 Elderly and Obese Patients

“…Additionally, it has been demonstrated that senescence markers (e.g., IL-6 production) was counteracted by resveratrol in neuroglial cells ( Bigagli et al, 2016 ), vascular smooth muscle cells ( Csiszar et al, 2012 ). Lastly, olive-derived polyphenols including oleuropein, found at very low level in edible table oil olive ( Ben Othman et al, 2008 ), significantly reduced the senescence in chondrocytes, synovial, and bone cells from osteoarthritic patients, an event that was accompanied by reduced activity of the NF-kB transcription factor and reduced SASP markers, as IL-6, IL-1β, and COX-2 ( Varela-Eirín et al, 2020 ).…”