Oxidized LDL accelerates cartilage destruction and inflammatory chondrocyte death in osteoarthritis by disrupting the TFEB-regulated autophagy-lysosome pathway

Journal article


Lee, J., Kim, Y., Jhun, J., Na, H., Um, In Gyu, Choi, J., Woo, J., Kim, S., Shetty, A., Kim, S. and Cho, M. 2024. Oxidized LDL accelerates cartilage destruction and inflammatory chondrocyte death in osteoarthritis by disrupting the TFEB-regulated autophagy-lysosome pathway. Immune Network. 24 (3). https://doi.org/10.4110/in.2024.24.e15
AuthorsLee, J., Kim, Y., Jhun, J., Na, H., Um, In Gyu, Choi, J., Woo, J., Kim, S., Shetty, A., Kim, S. and Cho, M.
Abstract

Osteoarthritis (OA) involves cartilage degeneration, thereby causing inflammation and pain. Cardiovascular diseases, such as dyslipidemia, are risk factors for OA; however, the mechanism is unclear. We investigated the effect of dyslipidemia on the development of OA. Treatment of cartilage cells with low-density lipoprotein (LDL) enhanced abnormal autophagy but suppressed normal autophagy and reduced the activity of transcription factor EB (TFEB), which is important for the function of lysosomes. Treatment of LDL-exposed chondrocytes with rapamycin, which activates TFEB, restored normal autophagy. Also, LDL enhanced the inflammatory death of chondrocytes, an effect reversed by rapamycin. In an animal model of hyperlipidemia-associated OA, dyslipidemia accelerated the development of OA, an effect reversed by treatment with a statin, an anti-dyslipidemia drug, or rapamycin, which activates TFEB. Dyslipidemia reduced the autophagic flux and induced necroptosis in the cartilage tissue of patients with OA. The levels of triglycerides, LDL, and total cholesterol were increased in patients with OA compared to those without OA. The C-reactive protein level of patients with dyslipidemia was higher than that of those without dyslipidemia after total knee replacement arthroplasty. In conclusion, oxidized LDL, an important risk factor of dyslipidemia, inhibited the activity of TFEB and reduced the autophagic flux, thereby inducing necroptosis in chondrocytes.

KeywordsOsteoarthritis; Dyslipidemia; Low-density lipoprotein; Autophagy; Necroptis
Year2024
JournalImmune Network
Journal citation24 (3)
PublisherThe Korean Association of Immunologists
ISSN1598-2629
2092-6685
Digital Object Identifier (DOI)https://doi.org/10.4110/in.2024.24.e15
Official URLhttps://immunenetwork.org/DOIx.php?id=10.4110/in.2024.24.e15
FunderNational Research Foundation of Korea
Korea Health Industry Development Institute
Publication dates
Online12 Apr 2024
Publication process dates
Accepted03 Apr 2024
Deposited08 Jul 2024
Output statusPublished
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https://repository.canterbury.ac.uk/item/98545/oxidized-ldl-accelerates-cartilage-destruction-and-inflammatory-chondrocyte-death-in-osteoarthritis-by-disrupting-the-tfeb-regulated-autophagy-lysosome-pathway

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