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Defective chaperone-mediated autophagy is a hallmark of joint disease in patients with knee osteoarthritis
dc.contributor.author | Lorenzo-Gómez, I. | |
dc.contributor.author | Nogueira Recalde, Uxía | |
dc.contributor.author | García-Domínguez, C. | |
dc.contributor.author | Oreiro, Natividad | |
dc.contributor.author | Lotz, Martin | |
dc.contributor.author | Pinto-Tasende, José A. | |
dc.contributor.author | Blanco García, Francisco J | |
dc.contributor.author | Caramés, Beatriz | |
dc.date.accessioned | 2023-04-12T06:49:55Z | |
dc.date.available | 2023-04-12T06:49:55Z | |
dc.date.issued | 2023-03-08 | |
dc.identifier.citation | Lorenzo-Gómez I, Nogueira-Recalde U, García-Domínguez C, Oreiro-Villar N, Lotz M, Pinto-Tasende JA, Blanco FJ, Caramés B. Defective chaperone-mediated autophagy is a hallmark of joint disease in patients with knee osteoarthritis. Osteoarthritis Cartilage. 2023 Jul;31(7):919-933. | es_ES |
dc.identifier.issn | 1063-4584 | |
dc.identifier.uri | http://hdl.handle.net/2183/32860 | |
dc.description.abstract | [Abstract] Objective: Defects in autophagy contribute to joint aging and Osteoarthritis (OA). Identifying specific autophagy types could be useful for developing novel treatments for OA. Design: An autophagy-related gene array was performed in blood from non-OA and knee OA subjects from the Prospective Cohort of A Coruña (PROCOAC). The differential expression of candidate genes was confirmed in blood and knee cartilage and a regression analysis was performed adjusting for age and BMI. HSP90A, a chaperone mediated autophagy (CMA) marker was validated in human knee joint tissues, as well as, in mice with aging-related and surgically-induced OA. The consequences of HSP90AA1 deficiency were evaluated on OA pathogenesis. Finally, the contribution of CMA to homeostasis was studied by assessing the capacity to restore proteostasis upon ATG5-mediated macroautophagy deficiency and genetic HSP90AA1 overexpression. Results: 16 autophagy-related genes were significantly down-regulated in blood from knee OA subjects. Validation studies showed that HSP90AA1 was down-regulated in blood and human OA cartilage and correlated with risk incidence of OA. Moreover, HSP90A was reduced in human OA joints tissues and with aging and OA in mice. HSP90AA1 knockdown was linked to defective macroautophagy, inflammation, oxidative stress, senescence and apoptosis. However, macroautophagy deficiency increased CMA, highlighting the CMA-macroautophagy crosstalk. Remarkably, CMA activation was sufficient to protect chondrocytes from damage. Conclusions: We show that HSP90A is a key chaperone for chondrocyte homeostasis, while defective CMA contributes to joint damage. We propose that CMA deficiency is a relevant disease mechanism and could represent a therapeutic target for OA. | es_ES |
dc.description.sponsorship | This study has been funded by Instituto de Salud Carlos III through the projects PI17/02059 and PI20/00643 and co-funded by the European Union. We thank the FOREUM Foundation for Research in Rheumatology for their support. ILG is supported by PI20/00643 project. UNR was supported by Ayudas de apoyo a la etapa de formación posdoctoral, Agencia Gallega de Innovación (GAIN), Xunta de Galicia, Spain, IN606B-2021/015. CGD was supported by Ayudas de apoyo a la etapa predoctoral, Adencia Gallega de Innovación (GAIN), Xunta de Galicia, IN606A-2022/028. BC was supported by Miguel Servet Type II Program – CPII16/00045-A, Instituto de Salud Carlos III, Ministerio de Ciencia, Innovación y Universidades, Servicio gallego de Salud (SERGAS), Spain. ML was supported by NIH grant AG059418. | es_ES |
dc.description.sponsorship | info:eu-repo/grantAgreement/ISCIII/Programa Estatal de Fomento de la Investigación Científica y Técnica de Excelencia/PI17%2F02059/ES/IDENTIFICACION Y VALIDACION DE DIANAS TERAPEUTICAS EN LA ARTROSIS ASOCIADA A DIABETES: PAPEL DE LA AUTOFAGIA | es_ES |
dc.description.sponsorship | info:eu-repo/grantAgreement/ISCIII/Programa Estatal de Generación de Conocimiento y Fortalecimiento del Sistema Español de I+D+I/PI20%2F00643/ES/AGONISTAS DE PPARA COMO TRATAMIENTO MODIFICADOR DE LA ENFERMEDAD PARA LA ARTROSIS | |
dc.description.sponsorship | Xunta de Galicia; IN606B-2021/015 | |
dc.description.sponsorship | info:eu-repo/grantAgreement/MINECO/Programa Estatal de I+D+I Orientada a los Retos de la Sociedad/CPII16%2F00045/ES/ | |
dc.language.iso | eng | es_ES |
dc.publisher | Elsevier | es_ES |
dc.relation.uri | https://doi.org/10.1016/j.joca.2023.02.076 | es_ES |
dc.rights | Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC-BY-NC-ND 4.0) | es_ES |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | * |
dc.subject | Aging | es_ES |
dc.subject | Chaperone mediated autophagy | es_ES |
dc.subject | Chondrocytes | es_ES |
dc.subject | Macroautophagy | es_ES |
dc.subject | Osteoarthritis | es_ES |
dc.title | Defective chaperone-mediated autophagy is a hallmark of joint disease in patients with knee osteoarthritis | es_ES |
dc.type | info:eu-repo/semantics/article | es_ES |
dc.rights.access | info:eu-repo/semantics/openAccess | es_ES |
UDC.journalTitle | Osteoarthritis and Cartilage | es_ES |
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