University of Oulu

Varela-Eirín, M., Carpintero-Fernández, P., Guitián-Caamaño, A. et al. Extracellular vesicles enriched in connexin 43 promote a senescent phenotype in bone and synovial cells contributing to osteoarthritis progression. Cell Death Dis 13, 681 (2022).

Extracellular vesicles enriched in connexin 43 promote a senescent phenotype in bone and synovial cells contributing to osteoarthritis progression

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Author: Varela-Eirín, Marta1,2; Carpintero-Fernández, Paula1; Guitián-Caamaño, Amanda1;
Organizations: 1CellCOM Research Group, Instituto de Investigación Biomédica de A Coruña (INIBIC), Servizo Galego de Saúde (SERGAS), Universidade da Coruña (UDC), A Coruña, Spain
2European Research Institute for the Biology of Ageing (ERIBA), University Medical Center Groningen (UMCG), University of Groningen (RUG), Groningen, The Netherlands
3Proteomics Laboratory, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complexo Hospitalario Universitario de Santiago de Compostela (CHUS), Universidade de Santiago de Compostela (USC), Santiago de Compostela, Spain
4Department of Orthopaedic Surgery and Traumatology, Complexo Hospitalario Universitario de Santiago de Compostela (CHUS), Universidade de Santiago de Compostela (USC), Santiago de Compostela, Spain
5Bone and Joint Research Unit, Rheumatology Department, IIS-Fundación Jiménez Díaz UAM, Madrid, Spain
6Research Unit of Medical Imaging, Physics and Technology, Faculty of Medicine, University of Oulu, Oulu, Finland
7Department of Regenerative Medicine, State Research Institute Centre for Innovative Medicine, Vilnius, Lithuania
8Departments of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
9Department of Joint Surgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
10World Health Organization Collaborating Centre for Public Health Aspects of Musculoskeletal Health and Aging, University of Liège, Liège, Belgium
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 7.6 MB)
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Language: English
Published: Springer Nature, 2022
Publish Date: 2023-03-20


The accumulation of senescent cells is a key characteristic of aging, leading to the progression of age-related diseases such as osteoarthritis (OA). Previous data from our laboratory has demonstrated that high levels of the transmembrane protein connexin 43 (Cx43) are associated with a senescent phenotype in chondrocytes from osteoarthritic cartilage. OA has been reclassified as a musculoskeletal disease characterized by the breakdown of the articular cartilage affecting the whole joint, subchondral bone, synovium, ligaments, tendons and muscles. However, the mechanisms that contribute to the spread of pathogenic factors throughout the joint tissues are still unknown. Here, we show for the first time that small extracellular vesicles (sEVs) released by human OA-derived chondrocytes contain high levels of Cx43 and induce a senescent phenotype in targeted chondrocytes, synovial and bone cells contributing to the formation of an inflammatory and degenerative joint environment by the secretion of senescence-associated secretory associated phenotype (SASP) molecules, including IL-1ß and IL-6 and MMPs. The enrichment of Cx43 changes the protein profile and activity of the secreted sEVs. Our results indicate a dual role for sEVs containing Cx43 inducing senescence and activating cellular plasticity in target cells mediated by NF-kß and the extracellular signal-regulated kinase 1/2 (ERK1/2), inducing epithelial-to-mesenchymal transition (EMT) signalling programme and contributing to the loss of the fully differentiated phenotype. Our results demonstrated that Cx43-sEVs released by OA-derived chondrocytes spread senescence, inflammation and reprogramming factors involved in wound healing failure to neighbouring tissues, contributing to the progression of the disease among cartilage, synovium, and bone and probably from one joint to another. These results highlight the importance for future studies to consider sEVs positive for Cx43 as a new biomarker of disease progression and new target to treat OA.

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Series: Cell death and disease
ISSN: 2041-4889
ISSN-E: 2041-4889
ISSN-L: 2041-4889
Volume: 13
Issue: 8
Article number: 681
DOI: 10.1038/s41419-022-05089-w
Type of Publication: A1 Journal article – refereed
Field of Science: 1182 Biochemistry, cell and molecular biology
3111 Biomedicine
Funding: This work was supported in part through funding from Health Institute ‘Carlos III’ (ISCIII, Spain), the European Regional Development Fund, ‘A way of making Europe’ from the European Union (to MDM): grant PI19/00145; a grant from the Joint Transnational Call for Proposals for “European Innovative Research & Technological Development Projects in Nanomedicine” EURONANOMED III (AC21_2/00026) (to MDM); a grant from Xunta de Galicia (IN607B2020/12) (to MDM) and from H2020, Future and Emerging Technologies (grant 858014 “PANACHE”) to MDM. MV-E was funded with a predoctoral (ED481A-2015/188) and post-doctoral fellowship (IN606B-2019/004) from Xunta de Galicia. AG-C was funded with a predoctoral fellowship (FIS20/00310) from ISCIII. PC-F was funded with a post-doctoral fellowship and a grant from Xunta de Galicia (INB606B 2017/014 and IN606C 2021/006). We thank members of the CellCOM group for helpful technical suggestion, María Dolores Álvarez Alvariño (CHUS) for generously collecting tissue samples in the operating room after surgery and Arantxa Tabernero (INCYL, University of Salamanca) for kindly providing the human Cx43 plasmid used in this study.
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