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Full Length Article | Open Access

Progranulin regulation of autophagy contributes to its chondroprotective effect in osteoarthritis

Yiming Pana,1, Yuyou Yanga,1, Mengtian Fana, Cheng Chenb, Rong Jiangc, Li Lianga, Menglin Xiana, Biao Kuangd, Nana Genga, Naibo Fenga, Lin Denga, Wei Zhenga, Fengmei Zhange, Xiaoli Lia, Fengjin Guoa( )
Department of Cell Biology and Genetics, Core Facility of Development Biology, Chongqing Medical University, Chongqing 400016, China
Department of Orthopaedics, The 1st Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
Laboratory of Stem Cells and Tissue Engineering, Chongqing Medical University, Chongqing 400016, China
Department of Orthopaedics, The 2nd Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
Chongqing Medical University Laboratory Animal Center, Chongqing Medical University, Chongqing 400016, China

Peer review under responsibility of Chongqing Medical University.

1 These authors contributed equally to this work.

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Abstract

Progranulin (PGRN) is a multifunctional growth factor involved in many physiological processes and disease states. The apparent protective role of PGRN and the importance of chondrocyte autophagic function in the progression of osteoarthritis (OA) led us to investigate the role of PGRN in the regulation of chondrocyte autophagy. PGRN knockout chondrocytes exhibited a deficient autophagic response with limited induction following rapamycin, serum starvation, and IL-1β-induced autophagy. PGRN-mediated anabolism and suppression of IL-1β-induced catabolism were largely abrogated in the presence of the BafA1 autophagy inhibitor. Mechanistically, during the process of OA, PGRN and the ATG5–ATG12 conjugate form a protein complex; PGRN regulates autophagy in chondrocytes and OA through, at least partially, the interactions between PGRN and the ATG5–ATG12 conjugate. Furthermore, the ATG5–ATG12 conjugate is critical for cell proliferation and apoptosis. Knockdown or knockout of ATG5 reduces the expression of ATG5–ATG12 conjugate and inhibits the chondroprotective effect of PGRN on anabolism and catabolism. Overexpression of PGRN partially reversed this effect. In brief, the PGRN-mediated regulation of chondrocyte autophagy plays a key role in the chondroprotective role of PGRN in OA. Such studies provide new insights into the pathogenesis of OA and PGRN-associated autophagy in chondrocyte homeostasis.

Keywords

OsteoarthritisAutophagyPGRNAnabolismATG12ATG5Catabolism

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Genes & Diseases
Volume 10 Issue 4,
July 2023
Pages 1582-1595
DOI: 10.1016/j.gendis.2022.05.031
Cite this article:
Pan Y, Yang Y, Fan M, et al. Progranulin regulation of autophagy contributes to its chondroprotective effect in osteoarthritis. Genes & Diseases, 2023, 10(4): 1582-1595. https://doi.org/10.1016/j.gendis.2022.05.031

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Received: 27 January 2022
Revised: 03 May 2022
Accepted: 21 May 2022
Published: 13 June 2022
© 2022 The Authors.

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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