Priority Research Paper|Volume 12, Issue 16|pp 15882—15905

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

Marta Varela-Eirín¹, Paula Carpintero-Fernández¹, Agustín Sánchez-Temprano¹, Adrián Varela-Vázquez¹, Carlos Luis Paíno², Antonio Casado-Díaz³, Alfonso Calañas-Continente³, Virginia Mato⁴, Eduardo Fonseca¹, Mustapha Kandouz⁵, Alfonso Blanco⁶, José Ramón Caeiro⁷, María D. Mayán¹

¹CellCOM Research Group, Instituto de Investigación Biomédica de A Coruña (INIBIC), Servizo Galego de Saúde (SERGAS), Universidade da Coruña (UDC), Xubias de Arriba, A Coruña, Spain
²Neurobiology-Research Service, Hospital Universitario Ramón y Cajal (IRYCIS), Madrid, Spain
³UGC Endocrinology and Nutrition, Maimónides Biomedical Research Institute of Córdoba (IMIBIC), Hospital Universitario Reina Sofía – CIBERFES, Universidad de Córdoba, Córdoba, Spain
⁴Centre for Medical Informatics and Radiological Diagnosis, Universidade da Coruña, A Coruña, Spain
⁵Department of Pathology, School of Medicine, Wayne State University, Detroit, MI 48202, USA
⁶Flow Cytometry Core Technologies, UCD Conway Institute, University College Dublin, Dublin, Ireland
⁷Department of Orthopaedic Surgery and Traumatology, Complexo Hospitalario Universitario de Santiago de Compostela (CHUS), Universidade de Santiago de Compostela (USC), Choupana s/n, Santiago de Compostela, Spain

Received: March 18, 2020Accepted: July 13, 2020Published: August 3, 2020

https://doi.org/10.18632/aging.103801

Copyright © 2020 Varela-Eirín et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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.