Immune Netw.
2024 Jun;24(3):e15. 10.4110/in.2024.24.e15.
Oxidized LDL Accelerates Cartilage Destruction and Inflammatory Chondrocyte Death in Osteoarthritis by Disrupting the TFEB-Regulated Autophagy-Lysosome Pathway
- Lee JS
1,2,3 - Kim YH4
- Jhun J1,2,3
- Na HS1,2
- Um IG1,2
- Choi JW1,2
- Woo JS1,2
- Kim SH4
- Shetty AA5
- Kim SJ4
- Cho ML1,2,3,6
- Affiliations
-
- 1The Rheumatism Research Center, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
- 2Lab of Translational ImmunoMedicine, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
- 3Department of Biomedicine and Health Sciences, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
- 4Department of Orthopedic Surgery, Uijeongbu St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
- 5Institute of Medical Sciences, Faculty of Health and Wellbeing, Medway Campus of Canterbury Christ Church University, Chatham ME4 4UF, UK
- 6Department of Medical Life Sciences, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
- KMID: 2557904
- DOI: http://doi.org/10.4110/in.2024.24.e15
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.
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