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
- 1 CellCOM 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
- 2 Neurobiology-Research Service, Hospital Universitario Ramón y Cajal (IRYCIS), Madrid, Spain
- 3 UGC Endocrinology and Nutrition, Maimónides Biomedical Research Institute of Córdoba (IMIBIC), Hospital Universitario Reina Sofía – CIBERFES, Universidad de Córdoba, Córdoba, Spain
- 4 Centre for Medical Informatics and Radiological Diagnosis, Universidade da Coruña, A Coruña, Spain
- 5 Department of Pathology, School of Medicine, Wayne State University, Detroit, MI 48202, USA
- 6 Flow Cytometry Core Technologies, UCD Conway Institute, University College Dublin, Dublin, Ireland
- 7 Department 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, 2020 Accepted: July 13, 2020 Published: August 3, 2020
https://doi.org/10.18632/aging.103801How to Cite
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.
Abbreviations
ACAN: aggrecan; AM: adipogenic medium; BC: bone cells; CBX: carbenoxolone; CD105: endoglin; CD166: CD166 antigen (ALCAM); CM: chondrogenic medium; CMT: chondrocyte-to-mesenchymal transition; Col2A1: collagen type II; COX-2: cyclooxygenase-2; Cx43: connexin43; CxREs: connexin-response elements; ECM: extracellular matrix; EMT: epithelial-to-mesenchymal transition; FDG: fluorescein-di-D-galactopyranoside; GJs: gap junctions; GJIC: gap junction intercellular communication; hMSCs: human mesenchymal stem cells; IL-1β: interleukin 1 beta; IL-6: interleukin 6; LY: Lucifer yellow; MMP-3: matrix metalloproteinase 3; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; OA: osteoarthritis; OACs: osteoarthritic chondrocytes; OE: olive extract; OM: osteogenic medium; Oleu: Oleuropein; OSTCN: osteocalcin; p16: cyclin-dependent kinase inhibitor 2A; p53: cellular tumour antigen p53; PPARγ: peroxisome proliferator-activated receptor gamma; RT-qPCR: real-time quantitative polymerase chain reaction; SA-βGal: senescence-associated β-galactosidase activity; SASP: senescence-associated secretory phenotype; SC: synovial cells; TNFα: tumour necrosis factor alpha; Twist-1: twist-related protein 1.