Journal
AGING-US
Volume 12, Issue 16, Pages 15882-15905Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/aging.103801
Keywords
senescence; dedifferentiation; osteoarthritis; connexin43; tissue regeneration
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Funding
- Spanish Foundation for Research on Bone and Mineral Metabolism (FEIOMM) from the FECYT-Ministry of Economy and Competitiveness [PRECIPITA2015-000139]
- Health Institute `Carlos III' (ISCIII, Spain) [PI16/00035, PI19/00145]
- European Regional Development Fund, 'A way of making Europe' from the European Union
- Xunta de Galicia [IN607B 2017/21, ED481A-2015/188, IN606B-2019/004, IN606B-2017/014]
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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-1 beta, 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.
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