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Oxidized LDL Accelerates Cartilage Destruction and Inflammatory Chondrocyte Death in Osteoarthritis by Disrupting the TFEB-Regulated Autophagy-Lysosome Pathway

  • Jeong Su Lee (The Rheumatism Research Center, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea) ;
  • Yun Hwan Kim (Department of Orthopedic Surgery, Uijeongbu St. Mary's Hospital, College of Medicine, The Catholic University of Korea) ;
  • JooYeon Jhun (The Rheumatism Research Center, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea) ;
  • Hyun Sik Na (The Rheumatism Research Center, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea) ;
  • In Gyu Um (The Rheumatism Research Center, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea) ;
  • Jeong Won Choi (The Rheumatism Research Center, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea) ;
  • Jin Seok Woo (The Rheumatism Research Center, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea) ;
  • Seung Hyo Kim (Department of Orthopedic Surgery, Uijeongbu St. Mary's Hospital, College of Medicine, The Catholic University of Korea) ;
  • Asode Ananthram Shetty (Institute of Medical Sciences, Faculty of Health and Wellbeing, Medway Campus of Canterbury Christ Church University) ;
  • Seok Jung Kim (Department of Orthopedic Surgery, Uijeongbu St. Mary's Hospital, College of Medicine, The Catholic University of Korea) ;
  • Mi-La Cho (The Rheumatism Research Center, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea)
  • Received : 2023.12.04
  • Accepted : 2024.04.03
  • Published : 2024.06.30
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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.

Keywords

Acknowledgement

This research was supported by the National Research Foundation of Korea grant funded by the Korea government (grant No. 2023R1A2C2003846). This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health & Welfare, Republic of Korea (grant No. HV22C0069).

References

  1. Hashimoto K, Akagi M. The role of oxidation of low-density lipids in pathogenesis of osteoarthritis: a narrative review. J Int Med Res 2020;48:300060520931609.
  2. de Munter W, Blom AB, Helsen MM, Walgreen B, van der Kraan PM, Joosten LA, van den Berg WB, van Lent PL. Cholesterol accumulation caused by low density lipoprotein receptor deficiency or a cholesterol-rich diet results in ectopic bone formation during experimental osteoarthritis. Arthritis Res Ther 2013;15:R178.
  3. Akkiraju H, Nohe A. Role of chondrocytes in cartilage formation, progression of osteoarthritis and cartilage regeneration. J Dev Biol 2015;3:177-192.
  4. Rellmann Y, Eidhof E, Dreier R. Review: ER stress-induced cell death in osteoarthritic cartilage. Cell Signal 2021;78:109880.
  5. Dai W, Cheng J, Leng X, Hu X, Ao Y. The potential role of necroptosis in clinical diseases (review). Int J Mol Med 2021;47:1-16.
  6. Duan R, Xie H, Liu ZZ. The role of autophagy in osteoarthritis. Front Cell Dev Biol 2020;8:608388.
  7. Funck-Brentano T, Nethander M, Moverare-Skrtic S, Richette P, Ohlsson C. Causal factors for knee, hip, and hand osteoarthritis: a Mendelian randomization study in the UK Biobank. Arthritis Rheumatol 2019;71:1634-1641.
  8. Linton MF, Yancey PG, Davies SS, Jerome WG, Linton EF, Song WL, Doran AC, Vickers KC. The role of lipids and lipoproteins in atherosclerosis. In: Feingold KR, Anawalt B, Blackman MR, Boyce A, Chrousos G, Corpas E, de Herder WW, Dhatariya K, Dungan K, Hofland J, et al., editors. Endotext. South Dartmouth, MA: MDText.com, Inc.; 2000.
  9. Nemet M, Blazin T, Milutinovic S, Cebovic T, Stanojevic D, Zvekic Svorcan J. Association between metabolic syndrome, its components, and knee osteoarthritis in premenopausal and menopausal women: a pilot study. Cureus 2022;14:e26726.
  10. Fang Z, Li X, Wang S, Jiang Q, Loor JJ, Jiang X, Ju L, Yu H, Shen T, Chen M, et al. Overactivation of hepatic mechanistic target of rapamycin kinase complex 1 (mTORC1) is associated with low transcriptional activity of transcription factor EB and lysosomal dysfunction in dairy cows with clinical ketosis. J Dairy Sci 2022;105:4520-4533.
  11. Schwager JL, Nevitt MC, Torner J, Lewis CE, Matthan NR, Wang N, Sun X, Lichtenstein AH, Felson D; Multicenter Osteoarthritis Study Group. Association of serum low-density lipoprotein, high-density lipoprotein, and total cholesterol with development of knee osteoarthritis. Arthritis Care Res (Hoboken) 2022;74:274-280.
  12. Nakagawa T, Yasuda T, Hoshikawa H, Shimizu M, Kakinuma T, Chen M, Masaki T, Nakamura T, Sawamura T. LOX-1 expressed in cultured rat chondrocytes mediates oxidized LDL-induced cell death-possible role of dephosphorylation of Akt. Biochem Biophys Res Commun 2002;299:91-97.
  13. Hashimoto K, Oda Y, Nakamura F, Kakinoki R, Akagi M. Lectin-like, oxidized low-density lipoprotein receptor-1-deficient mice show resistance to age-related knee osteoarthritis. Eur J Histochem 2017;61:2762.
  14. Akagi M, Kanata S, Mori S, Itabe H, Sawamura T, Hamanishi C. Possible involvement of the oxidized low-density lipoprotein/lectin-like oxidized low-density lipoprotein receptor-1 system in pathogenesis and progression of human osteoarthritis. Osteoarthritis Cartilage 2007;15:281-290.
  15. Cao C, Shi Y, Zhang X, Li Q, Zhang J, Zhao F, Meng Q, Dai W, Liu Z, Yan W, et al. Cholesterol-induced LRP3 downregulation promotes cartilage degeneration in osteoarthritis by targeting Syndecan-4. Nat Commun 2022;13:7139.
  16. Choi WS, Lee G, Song WH, Koh JT, Yang J, Kwak JS, Kim HE, Kim SK, Son YO, Nam H, et al. The CH25HCYP7B1-RORα axis of cholesterol metabolism regulates osteoarthritis. Nature 2019;566:254-258.
  17. Shen P, Zhu Y, Zhu L, Weng F, Li X, Xu Y. Oxidized low density lipoprotein facilitates tumor necrosis factor-α mediated chondrocyte death via autophagy pathway. Mol Med Rep 2017;16:9449-9456.
  18. Luo P, Gao F, Niu D, Sun X, Song Q, Guo C, Liang Y, Sun W. The role of autophagy in chondrocyte metabolism and osteoarthritis: a comprehensive research review. BioMed Res Int 2019;2019:5171602.
  19. Carames B, Taniguchi N, Otsuki S, Blanco FJ, Lotz M. Autophagy is a protective mechanism in normal cartilage, and its aging-related loss is linked with cell death and osteoarthritis. Arthritis Rheum 2010;62:791-801.
  20. Sun K, Guo Z, Zhang J, Hou L, Liang S, Lu F, Wang G, Xu J, Zhang X, Guo F, et al. Inhibition of TRADD ameliorates chondrocyte necroptosis and osteoarthritis by blocking RIPK1-TAK1 pathway and restoring autophagy. Cell Death Dis 2023;9:109.
  21. Zhang H, Ge S, Ni B, He K, Zhu P, Wu X, Shao Y. Augmenting ATG14 alleviates atherosclerosis and inhibits inflammation via promotion of autophagosome-lysosome fusion in macrophages. Autophagy 2021;17:4218-4230.
  22. Qin X, He W, Yang R, Liu L, Zhang Y, Li L, Si J, Li X, Ma K. Inhibition of Connexin 43 reverses ox-LDL-mediated inhibition of autophagy in VSMC by inhibiting the PI3K/Akt/mTOR signaling pathway. PeerJ 2022;10:e12969.
  23. Zhang Q, Cao S, Qiu F, Kang N. Incomplete autophagy: trouble is a friend. Med Res Rev 2022;42:1545-1587.
  24. Martina JA, Chen Y, Gucek M, Puertollano R. MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB. Autophagy 2012;8:903-914.
  25. Tan A, Prasad R, Lee C, Jho EH. Past, present, and future perspectives of transcription factor EB (TFEB): mechanisms of regulation and association with disease. Cell Death Differ 2022;29:1433-1449.
  26. Akhmedov A, Camici GG, Reiner MF, Bonetti NR, Costantino S, Holy EW, Spescha RD, Stivala S, Schaub Clerigue A, Speer T, et al. Endothelial LOX-1 activation differentially regulates arterial thrombus formation depending on oxLDL levels: role of the Oct-1/SIRT1 and ERK1/2 pathways. Cardiovasc Res 2017;113:498-507.
  27. Zhang Z, Yue P, Lu T, Wang Y, Wei Y, Wei X. Role of lysosomes in physiological activities, diseases, and therapy. J Hematol Oncol 2021;14:79.
  28. Tao J, Yang P, Xie L, Pu Y, Guo J, Jiao J, Sun L, Lu D. Gastrodin induces lysosomal biogenesis and autophagy to prevent the formation of foam cells via AMPK-FoxO1-TFEB signalling axis. J Cell Mol Med 2021;25:5769-5781.
  29. Zhou YD, Cao XQ, Liu ZH, Cao YJ, Liu CF, Zhang YL, Xie Y. Rapamycin inhibits oxidized low density lipoprotein uptake in human umbilical vein endothelial cells via mTOR/NF-κB/LOX-1 pathway. PLoS One 2016;11:e0146777.
  30. Xu C, Wu J, Wu Y, Ren Z, Yao Y, Chen G, Fang EF, Noh JH, Liu YU, Wei L, et al. TNF-α-dependent neuronal necroptosis regulated in Alzheimer's disease by coordination of RIPK1-p62 complex with autophagic UVRAG. Theranostics 2021;11:9452-9469.
  31. Karunakaran D, Geoffrion M, Wei L, Gan W, Richards L, Shangari P, DeKemp EM, Beanlands RA, Perisic L, Maegdefessel L, et al. Targeting macrophage necroptosis for therapeutic and diagnostic interventions in atherosclerosis. Sci Adv 2016;2:e1600224.
  32. Steinl DC, Kaufmann BA. Ultrasound imaging for risk assessment in atherosclerosis. Int J Mol Sci 2015;16:9749-9769.
  33. Hashimoto K, Mori S, Oda Y, Nakano A, Sawamura T, Akagi M. Lectin-like oxidized low density lipoprotein receptor 1-deficient mice show resistance to instability-induced osteoarthritis. Scand J Rheumatol 2016;45:412-422.
  34. de Munter W, van den Bosch MH, Sloetjes AW, Croce KJ, Vogl T, Roth J, Koenders MI, van de Loo FA, van den Berg WB, van der Kraan PM, et al. High LDL levels lead to increased synovial inflammation and accelerated ectopic bone formation during experimental osteoarthritis. Osteoarthritis Cartilage 2016;24:844-855.
  35. Monetti M, Canavesi M, Camera M, Parente R, Paoletti R, Tremoli E, Corsini A, Bellosta S. Rosuvastatin displays anti-atherothrombotic and anti-inflammatory properties in ApoE-deficient mice. Pharmacol Res 2007;55:441-449.
  36. Sironi L, Gianazza E, Gelosa P, Guerrini U, Nobili E, Gianella A, Cremonesi B, Paoletti R, Tremoli E. Rosuvastatin, but not simvastatin, provides end-organ protection in stroke-prone rats by antiinflammatory effects. Arterioscler Thromb Vasc Biol 2005;25:598-603.
  37. Yudoh K, Karasawa R. Statin prevents chondrocyte aging and degeneration of articular cartilage in osteoarthritis (OA). Aging (Albany NY) 2010;2:990-998.
  38. Carames B, Hasegawa A, Taniguchi N, Miyaki S, Blanco FJ, Lotz M. Autophagy activation by rapamycin reduces severity of experimental osteoarthritis. Ann Rheum Dis 2012;71:575-581.
  39. Hall AJ, Stubbs B, Mamas MA, Myint PK, Smith TO. Association between osteoarthritis and cardiovascular disease: systematic review and meta-analysis. Eur J Prev Cardiol 2016;23:938-946.
  40. Zushi S, Akagi M, Kishimoto H, Teramura T, Sawamura T, Hamanishi C. Induction of bovine articular chondrocyte senescence with oxidized low-density lipoprotein through lectin-like oxidized low-density lipoprotein receptor 1. Arthritis Rheum 2009;60:3007-3016.
  41. Akagi M, Ueda A, Teramura T, Kanata S, Sawamura T, Hamanishi C. Oxidized LDL binding to LOX-1 enhances MCP-1 expression in cultured human articular chondrocytes. Osteoarthritis Cartilage 2009;17:271-275.
  42. Farnaghi S, Crawford R, Xiao Y, Prasadam I. Cholesterol metabolism in pathogenesis of osteoarthritis disease. Int J Rheum Dis 2017;20:131-140.
  43. Jin X, Beguerie JR, Zhang W, Blizzard L, Otahal P, Jones G, Ding C. Circulating C reactive protein in osteoarthritis: a systematic review and meta-analysis. Ann Rheum Dis 2015;74:703-710.
  44. Nie P, Yang F, Wan F, Jin S, Pu J. Analysis of microRNAs associated with carotid atherosclerotic plaque rupture with thrombosis. Front Genet 2021;12:599350.
  45. Herrero-Manley L, Alabajos-Cea A, Suso-Marti L, Cuenca-Martinez F, Calatayud J, Casana J, Viosca-Herrero E, Vazquez-Arce I, Ferrer-Sargues FJ, Blanco-Diaz M. Serum lipid biomarkers and inflammatory cytokines associated with onset and clinical status of patients with early knee osteoarthritis. Front Nutr 2023;10:1126796.