POS0226 DEFICIENT CHAPERONE-MEDIATED AUTOPHAGY CONTRIBUTES TO JOINT DAMAGE IN OSTEOARTHRITIS
| Autor: | I. Lorenzo, U. Nogueira-Recalde, C. Garcia-Dominguez, N. Oreiro, J. A. Pinto Tasende, M. Lotz, F. J. Blanco, B. Carames |
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| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | Annals of the Rheumatic Diseases. 81:349.1-350 |
| ISSN: | 1468-2060 0003-4967 |
| DOI: | 10.1136/annrheumdis-2022-eular.1939 |
| Popis: | BackgroundIn Osteoarthritis (OA), defects in macroautophagy are evident and precede joint damage. Indeed, pharmacological activation of macroautophagy protects against joint damage and disease.ObjectivesTherefore, identifying hallmarks associated with specific autophagy subtypes could shed light to fundamental mechanisms of joint disease and facilitate the development of therapeutic strategies to prevent OA progression.MethodsA gene expression analysis of 35 autophagy genes was performed from blood from a Prospective OA Cohort of A Coruña (PROCOAC) of non-OA (Age:61,44±1,16 years; BMI:25,25±0,52; Females, n=18) and knee OA subjects (Age:65,50±1,05 years; BMI:29,55±0,67; Females, n=18, OA grade III-IV) by using SYBR green array. The differential expression of candidate genes in blood (n=30/group) and knee cartilage (Non-OA, n=12; Knee OA donors, n=21) was confirmed by using Taqman Technology. HSP90AA1, a chaperone mediated autophagy (CMA) mediator, was evaluated in human knee joint tissues (i.e. cartilage, meniscus, ACL and synovium) with different KL grades (0, 2 and 4, n=3/each KL grade) and in both spontaneous aging mice (2, 6, 12, 18, and 30 months old, n=3/each time) and surgically-induced OA mice (10 weeks after surgery, n=4/each) by immunohistochemistry. The functional consequences of HSP90AA1 deficiency on inflammation, oxidative stress, senescence and apoptosis were studied in human OA chondrocytes by gene and protein expression and flow cytometry. The potential contribution of CMA to chondrocyte homeostasis was studied by assessing the capacity of CMA to restore proteostasis upon macroautophagy deficiency by ATG5 knockdown. To study the therapeutic potential of targeting CMA, HSP90AA1 was overexpressed in human OA chondrocytes.Results16 autophagy-related genes were significantly downregulated in knee OA subjects (pConclusionTaking together, we identified HSP90A, a marker of CMA, as a key regulator of chondrocyte homeostasis underlying a relevant mechanism in OA. A better definition of the cross-talk between CMA and macroautophagy defects might reveal its role as a hallmark of OA.References[1]Caramés B, et al. Arthritis Rheum. 2010, 2015; 2. Caramés B, et al. Ann Rheum Dis. 2012Disclosure of InterestsNone declared |
| Databáze: | OpenAIRE |
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