1. Senolytic Activity of Small Molecular Polyphenols from Olive Restores Chondrocyte Redifferentiation and Promotes a Pro-Regenerative Environment in Osteoarthritis
- Author
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Alfonso Blanco, Antonio Casado-Díaz, Paula Carpintero-Fernández, Agustín Sánchez-Temprano, Mustapha Kandouz, M. Varela-Eirin, Maria D. Mayan, Adrian Varela-Vazquez, Alfonso Calañas Continente, Eduardo Fonseca, José R. Caeiro, Carlos L. Paíno, and Virginia Mato
- Subjects
Cartilage, Articular ,Male ,Aging ,senescence ,Iridoid Glucosides ,tissue regeneration ,Senescence ,Regenerative medicine ,Chondrocyte ,Cell Line ,Chondrocytes ,Tissue engineering ,Osteogenesis ,Olea ,Bone cell ,Osteoarthritis ,medicine ,Humans ,Regeneration ,Connexin43 ,Iridoids ,Senolytic ,Collagen Type II ,Cellular Senescence ,Aged ,Chemistry ,Cartilage ,dedifferentiation ,Twist-Related Protein 1 ,NF-kappa B ,Nuclear Proteins ,Polyphenols ,Cell Differentiation ,Cell Biology ,Chondrogenesis ,connexin43 ,Cell biology ,medicine.anatomical_structure ,Cellular Microenvironment ,Adipogenesis ,Antirheumatic Agents ,Connexin 43 ,Fruit ,Tissue regeneration ,Female ,Dedifferentiation ,Priority Research Paper ,Signal Transduction - Abstract
[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. Xunta de Galicia; IN607B 2017/21 Xunta de Galicia; ED481A-2015/188 Xunta de Galicia; IN606B-2019/004 Xunta de Galicia; IN606B-2017/014 This work was supported in part through funding from the Spanish Foundation for Research on Bone and Mineral Metabolism (FEIOMM), grant PRECIPITA-2015-000139 from the FECYT-Ministry of Economy and Competitiveness (to M.D.M.), grant PI16/00035 and PI19/00145 from the Health Institute ‘Carlos III’ (ISCIII, Spain), the European Regional Development Fund, ‘A way of making Europe’ from the European Union (to M.D.M.) and a grant from Xunta de Galicia IN607B 2017/21 (to M.D.M.). M.V.-E. was funded with a predoctoral (ED481A-2015/188) and a postdoctoral fellowship (IN606B-2019/004) from Xunta de Galicia. P.C.-F. was funded with a postdoctoral fellowship (IN606B-2017/014) from Xunta de Galicia.
- Published
- 2020