Defective chaperone-mediated autophagy is a hallmark of joint disease in patients with knee osteoarthritis

被引：15

作者：

Lorenzo-Gomez, I. ^{[1
]}

Nogueira-Recalde, U. ^{[1
]}

Garcia-Dominguez, C. ^{[1
]}

Oreiro-Villar, N. ^{[2
]}

Lotz, M. ^{[3
]}

Pinto-Tasende, J. A. ^{[2
]}

Blanco, F. J. ^{[1
,2
]}

Carames, B. ^{[1
,4
]}

机构：

[1] Univ Coruna UDC, Complejo Hosp Univ A Coruna CHUAC, Inst Invest Biomed A Coruna INIBIC, Unidad Biol Cartilago,Grp Invest Reumatol GIR, La Coruna, Spain

[2] CHUAC, Unidad Reumatol Clin, GIR, La Coruna, Spain

[3] Scripps Res, Dept Mol Med, La Jolla, CA USA

[4] Univ Coruna UDC, Inst Invest Biomed A Coruna INIBIC, CHUAC, Unidad Biol Cartilago,Grp Invest Reumatol, As Xubias 84, La Coruna 15006, Spain

来源：

OSTEOARTHRITIS AND CARTILAGE | 2023年 / 31卷 / 07期

关键词：

Chaperone mediated autophagy; Macroautophagy; Chondrocytes; Aging; Osteoarthritis; CARTILAGE; ACTIVATION; MACROAUTOPHAGY; RECEPTOR; COMPLEX; AGE;

D O I：

10.1016/j.joca.2023.02.076

中图分类号：

R826.8 [整形外科学]; R782.2 [口腔颌面部整形外科学]; R726.2 [小儿整形外科学]; R62 [整形外科学（修复外科学）];

学科分类号：

摘要：

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 Corun(similar to)a (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 defi-ciency 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, inflamma-tion, 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. (c) 2023 The Author(s). Published by Elsevier Ltd on behalf of Osteoarthritis Research Society International. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).

引用

页码：919 / 933

页数：15

共 55 条

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