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Journal of molecular medicine (Berlin, Germany)
10, 2024;102 (10): 1229-1244.

New insights into the mechanisms and therapeutic strategies of chondrocyte autophagy in osteoarthritis.

Lujia Tang, Jiatong Ding, Kangping Yang, Zhen Zong, Rui Wu, Hui Li
Author Information
  1. Lujia Tang: Department of Rheumatology and Immunology, The First Affiliated Hospital of Nanchang University, Nanchang, China.
  2. Jiatong Ding: Department of Rheumatology and Immunology, The First Affiliated Hospital of Nanchang University, Nanchang, China.
  3. Kangping Yang: Department of Rheumatology and Immunology, The First Affiliated Hospital of Nanchang University, Nanchang, China.
  4. Zhen Zong: Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China.
  5. Rui Wu: Department of Rheumatology and Immunology, The First Affiliated Hospital of Nanchang University, Nanchang, China. tcmclinic@163.com.
  6. Hui Li: Department of Rheumatology and Immunology, The First Affiliated Hospital of Nanchang University, Nanchang, China. ndyfy04408@ncu.edu.cn. ORCID
PMID: 39145815 DOI: 10.1007/s00109-024-02473-1

Abstract

Osteoarthritis (OA) is a chronic joint disease with an unclear cause characterized by secondary osteophytes and degenerative changes in the articular cartilage. More than 250 million people are expected to be affected by it by 2050, putting a tremendous socioeconomic strain on the entire world. OA cannot currently be treated with any effective medications that change the illness. Over time, chondrocytes undergo gradual metabolic, structural, and functional changes as a result of aging or abuse. The degenerative progression of osteoarthritis is significantly influenced by the imbalance of chondrocyte homeostasis. By continuously recycling and rebuilding macromolecules or organelles, autophagy functions as a crucial regulatory system to maintain homeostasis during an individual's growth and development. This review uses chondrocytes as its starting point and establishes a strong connection between autophagy and osteoarthritis in order to thoroughly examine the mechanisms behind chondrocyte autophagy in osteoarthritis. Biomarkers of chondrocyte autophagy will be identified, and prospective targeted medications and novel treatment approaches for slowing or preventing the course of OA will be developed based on chondrocyte senescence, autophagy, and apoptosis in OA. KEY MESSAGES: Currently, OA has not been treated with any drugs that can effectively cure it. We hope that by exploring specific targets in the course of osteoarthritis, we can promote the progress of treatment strategies. The degenerative progression of osteoarthritis is significantly influenced by the imbalance of chondrocyte balance. Through the continuous recovery and reconstruction of macromolecules or organelles, autophagy is an important regulatory system for maintaining homeostasis during individual growth and development. In this paper, the close relationship between autophagy and osteoarthritis was established with chondrocytes as the starting point, in order to further explore the mechanism of chondrocyte autophagy in osteoarthritis. The development process of osteoarthritis was studied from the perspective of chondrocytes, and the change of autophagy level had a significant impact on osteoarthritis. Chondrocyte autophagy is mainly determined by intracellular mitochondrial autophagy, so we are committed to finding relevant molecules. Through PI3K/AKT- and MAPK-related pathways, the biomarkers of chondrocyte autophagy were identified, and chondrocyte senescence, autophagy, and apoptosis based on osteoarthritis provided a constructive idea for the development of prospective targeted drugs and new therapies to slow down or prevent the progression of osteoarthritis.

Keywords

Autophagy Chondrocyte Osteoarthritis

References

  1. Nasui BA, Talaba P, Nasui GA, Sirbu DM, Borda IM, Pop ALet al (2022) The influence of diet and physical activity on oxidative stress in romanian females with osteoarthritis. Nutrients, 14:(19)4159
  2. Sewell J, ��st��r A (2022) Emerging injectable therapies for osteoarthritis. Expert Opin Emerg Drugs 27:311���320 [PMID: 36102303]
  3. Yao Q, Wu X, Tao C, Gong W, Chen M, Qu M et al (2023) Osteoarthritis: pathogenic signaling pathways and therapeutic targets. Signal Transduct Target Ther 8:56 [PMID: 36737426]
  4. Dantas LO, Salvini TF, McAlindon TE (2021) Knee osteoarthritis: key treatments and implications for physical therapy. Braz J Phys Ther 25:135���146 [PMID: 33262080]
  5. Jang S, Lee K, Ju JH (2021) Recent updates of diagnosis, pathophysiology, and treatment on osteoarthritis of the knee. International J Mol Sci 22(5):2619
  6. Allen KD, Thoma LM, Golightly YM (2022) Epidemiology of osteoarthritis Osteoarthritis and cartilage 30:184���195 [PMID: 34534661]
  7. Motta F, Barone E, Sica A, Selmi C (2023) Inflammaging and osteoarthritis. Clin Rev Allergy Immunol 64:222���238 [PMID: 35716253]
  8. Kuang X, Chiou J, Lo K, Wen C (2021) Magnesium in joint health and osteoarthritis. Nutr Res (New York, NY) 90:24���35 [DOI: 10.1016/j.nutres.2021.03.002]
  9. Tong L, Yu H, Huang X, Shen J, Xiao G, Chen L et al (2022) Current understanding of osteoarthritis pathogenesis and relevant new approaches. Bone research 10:60 [PMID: 36127328]
  10. Zhuang SZ, Chen PJ, Han J, Xiao WH (2023) Beneficial effects and potential mechanisms of tai chi on lower limb osteoarthritis: a biopsychosocial perspective. Chin J Integr Med 29:368���376 [PMID: 34921649]
  11. Fonseca-Rodrigues D, Rodrigues A, Martins T, Pinto J, Amorim D, Almeida A et al (2021) Correlation between pain severity and levels of anxiety and depression in osteoarthritis patients: a systematic review and meta-analysis. Rheumatology (Oxford) 61:53���75 [PMID: 34152386]
  12. Wang Z, Kang C, Xu P, Zhang S, Song JH, Wang D et al (2022) Osteoarthritis and cardiovascular disease: a Mendelian randomization study. Front Cardiovasc Med 9:1025063 [PMID: 36465459]
  13. Xiao Q, Cai B, Yin A, Huo H, Lan K, Zhou G et al (2022) L-shaped association of serum 25-hydroxyvitamin D concentrations with cardiovascular and all-cause mortality in individuals with osteoarthritis: results from the NHANES database prospective cohort study. BMC Med 20:308 [PMID: 36127705]
  14. Vina ER, Kwoh CK (2018) Epidemiology of osteoarthritis: literature update. Curr Opin Rheumatol 30:160���167 [PMID: 29227353]
  15. Brumat P, Kun��i�� O, Novak S, Slokar U, P��enica J, Topolovec Met al (2022) The surgical treatment of osteoarthritis. Life Basel, Switzerland 12(7):982
  16. Duan R, Xie H, Liu ZZ (2020) The role of autophagy in osteoarthritis. Front Cell Dev Biol 8:608388 [PMID: 33324654]
  17. Sacitharan PK (2019) Ageing and Osteoarthritis. Subcell Biochem 91:123���159 [PMID: 30888652]
  18. Liu Y, Zhang Z, Li T, Xu H, Zhang H (2022) Senescence in osteoarthritis: from mechanism to potential treatment. Arthritis Res Ther 24:174 [PMID: 35869508]
  19. Fujii Y, Liu L, Yagasaki L, Inotsume M, Chiba T, Asahara H (2022) Cartilage homeostasis and osteoarthritis. Int J Mol Sci 23(11):6316
  20. Zheng L, Zhang Z, Sheng P, Mobasheri A (2021) The role of metabolism in chondrocyte dysfunction and the progression of osteoarthritis. Ageing Res Rev 66:101249 [PMID: 33383189]
  21. Iijima H, Gilmer G, Wang K, Bean AC, He Y, Lin H et al (2023) Age-related matrix stiffening epigenetically regulates ��-Klotho expression and compromises chondrocyte integrity. Nat Commun 14:18 [PMID: 36627269]
  22. Wakale S, Wu X, Sonar Y, Sun A, Fan X, Crawford R et al (2023) How are aging and osteoarthritis related? Aging Dis 14:592���604 [PMID: 37191424]
  23. Lv X, Zhao T, Dai Y, Shi M, Huang X, Wei Y et al (2022) New insights into the interplay between autophagy and cartilage degeneration in osteoarthritis. Front Cell Dev Biol 10:1089668 [PMID: 36544901]
  24. Kao WC, Chen JC, Liu PC, Lu CC, Lin SY, Chuang SC et al (2022) The role of autophagy in osteoarthritic cartilage. Biomolecules 12(10):1357
  25. Kaushik S, Tasset I, Arias E, Pampliega O, Wong E, Martinez-Vicente M et al (2021) Autophagy and the hallmarks of aging. Ageing Res Rev 72:101468 [PMID: 34563704]
  26. Trojani MC, Santucci-Darmanin S, Breuil V, Carle GF, Pierrefite-Carle V (2022) Autophagy and bone diseases. Joint Bone Spine 89:105301 [PMID: 34673234]
  27. Ren J, Zhang Y (2018) Targeting autophagy in aging and aging-related cardiovascular diseases. Trends Pharmacol Sci 39:1064���1076 [PMID: 30458935]
  28. Klionsky DJ, Abdel-Aziz AK, Abdelfatah S, Abdellatif M, Abdoli A, Abel S et al (2021) Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)(1). Autophagy 17:1���382 [PMID: 33634751]
  29. Margeta M (2020) Autophagy defects in skeletal myopathies. Annu Rev Pathol 15:261���285 [PMID: 31594457]
  30. Luo P, Gao F, Niu D, Sun X, Song Q, Guo C et al (2019) The role of autophagy in chondrocyte metabolism and osteoarthritis: a comprehensive research review. Biomed Res Int 2019:5171602 [PMID: 31111057]
  31. Nie T, Zhu L, Yang Q (2021) The classification and basic processes of autophagy. Adv Exp Med Biol 1208:3���16 [PMID: 34260018]
  32. Levine B, Kroemer G (2019) Biological functions of autophagy genes: a disease perspective. Cell 176:11���42 [PMID: 30633901]
  33. Schuck S (2020) Microautophagy - distinct molecular mechanisms handle cargoes of many sizes. J Cell Sci 133(17):jcs246322
  34. Yang Q, Wang R, Zhu L (2019) Chaperone-mediated autophagy. Adv Exp Med Biol 1206:435���452 [PMID: 31776997]
  35. Kaushik S, Cuervo AM (2018) The coming of age of chaperone-mediated autophagy. Nat Rev Mol Cell Biol 19:365���381 [PMID: 29626215]
  36. Aman Y, Schmauck-Medina T, Hansen M, Morimoto RI, Simon AK, Bjedov I et al (2021) Autophagy in healthy aging and disease. Nature Aging 1:634���650 [PMID: 34901876]
  37. Deretic V (2021) Autophagy in inflammation, infection, and immunometabolism. Immunity 54:437���453 [PMID: 33691134]
  38. Kitada M, Koya D (2021) Autophagy in metabolic disease and ageing. Nat Rev Endocrinol 17:647���661 [PMID: 34508250]
  39. Gong Y, Li S, Wu J, Zhang T, Fang S, Feng D et al (2023) Autophagy in the pathogenesis and therapeutic potential of post-traumatic osteoarthritis. Burns Trauma 11:tkac060 [PMID: 36733467]
  40. Wang J, Zhang Y, Cao J, Wang Y, Anwar N, Zhang Z et al (2023) The role of autophagy in bone metabolism and clinical significance. Autophagy 19:2409���2427 [PMID: 36858962]
  41. Menon MB, Dhamija S (2018) Beclin 1 Phosphorylation - at the center of autophagy regulation. Front Cell Dev Biol 6:137 [PMID: 30370269]
  42. Aslan E, K������ko��lu N, Arslanyolu M (2017) A comparative in-silico analysis of autophagy proteins in ciliates. PeerJ 5:e2878 [PMID: 28123910]
  43. Caram��s B, Taniguchi N, Otsuki S, Blanco FJ, Lotz M (2010) Autophagy is a protective mechanism in normal cartilage, and its aging-related loss is linked with cell death and osteoarthritis. Arthritis Rheum 62:791���801 [PMID: 20187128]
  44. Liu D, Cai ZJ, Yang YT, Lu WH, Pan LY, Xiao WF et al (2022) Mitochondrial quality control in cartilage damage and osteoarthritis: new insights and potential therapeutic targets. Osteoarthritis Cartilage 30:395���405 [PMID: 34715366]
  45. Lu J, Peng Y, Zou J, Wang J, Lu S, Fu T et al (2021) Hypoxia inducible factor-1�� is a regulator of autophagy in osteoarthritic chondrocytes. Cartilage 13:1030s-s1040 [PMID: 34459260]
  46. Bolduc JA, Collins JA, Loeser RF (2019) Reactive oxygen species, aging and articular cartilage homeostasis. Free Radical Biol Med 132:73���82 [DOI: 10.1016/j.freeradbiomed.2018.08.038]
  47. Coryell PR, Diekman BO, Loeser RF (2021) Mechanisms and therapeutic implications of cellular senescence in osteoarthritis. Nat Rev Rheumatol 17:47���57 [PMID: 33208917]
  48. Pickles S, Vigi�� P, Youle RJ (2018) Mitophagy and quality control mechanisms in mitochondrial maintenance. Current biology���: CB 28:R170���R185 [PMID: 29462587]
  49. Palikaras K, Lionaki E, Tavernarakis N (2018) Mechanisms of mitophagy in cellular homeostasis, physiology and pathology. Nat Cell Biol 20:1013���1022 [PMID: 30154567]
  50. Li X, He S, Ma B (2020) Autophagy and autophagy-related proteins in cancer. Mol Cancer 19:12 [PMID: 31969156]
  51. Strubbe-Rivera JO, Schrad JR, Pavlov EV, Conway JF, Parent KN, Bazil JN (2021) The mitochondrial permeability transition phenomenon elucidated by cryo-EM reveals the genuine impact of calcium overload on mitochondrial structure and function. Sci Rep 11:1037 [PMID: 33441863]
  52. Guo JY, Chen HY, Mathew R, Fan J, Strohecker AM, Karsli-Uzunbas G et al (2011) Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis. Genes Dev 25:460���470 [PMID: 21317241]
  53. Abate M, Festa A, Falco M, Lombardi A, Luce A, Grimaldi A et al (2020) Mitochondria as playmakers of apoptosis, autophagy and senescence. Semin Cell Dev Biol 98:139���153 [PMID: 31154010]
  54. Kan S, Duan M, Liu Y, Wang C, Xie J (2021) Role of mitochondria in physiology of chondrocytes and diseases of osteoarthritis and rheumatoid arthritis. Cartilage 13:1102s-s1121 [PMID: 34894777]
  55. Song H, Park KH (2020) Regulation and function of SOX9 during cartilage development and regeneration. Semin Cancer Biol 67:12���23 [PMID: 32380234]
  56. Sun K, Luo J, Guo J, Yao X, Jing X, Guo F (2020) The PI3K/AKT/mTOR signaling pathway in osteoarthritis: a narrative review. Osteoarthritis Cartilage 28:400���409 [PMID: 32081707]
  57. Coryell PR, Goraya SK, Griffin KA, Redick MA, Sisk SR, Purvis JE (2020) Autophagy regulates the localization and degradation of p16(INK4a). Aging Cell 19:e13171 [PMID: 32662244]
  58. Katz JN, Arant KR, Loeser RF (2021) Diagnosis and treatment of hip and knee osteoarthritis: a review. JAMA 325:568���578 [PMID: 33560326]
  59. Pigeolet M, Jayaram A, Park KB, Meara JG (2021) Osteoarthritis in 2020 and beyond. Lancet (London, England) 397:1059���1060 [PMID: 33743863]
  60. Liu Z, Wang T, Sun X, Nie M (2023) Autophagy and apoptosis: regulatory factors of chondrocyte phenotype transition in osteoarthritis. Hum Cell 36:1326���1335 [PMID: 37277675]
  61. Ansari MY, Khan NM, Ahmad I, Haqqi TM (2018) Parkin clearance of dysfunctional mitochondria regulates ROS levels and increases survival of human chondrocytes. Osteoarthritis Cartilage 26:1087���1097 [PMID: 28801211]
  62. Wang C, Yang Y, Zhang Y, Liu J, Yao Z, Zhang C (2019) Protective effects of metformin against osteoarthritis through upregulation of SIRT3-mediated PINK1/Parkin-dependent mitophagy in primary chondrocytes. Biosci Trends 12:605���612 [PMID: 30584213]
  63. Sun K, Jing X, Guo J, Yao X, Guo F (2021) Mitophagy in degenerative joint diseases. Autophagy 17:2082���2092 [PMID: 32967533]
  64. Zeng Z, Zhou X, Wang Y, Cao H, Guo J, Wang P et al (2022) Mitophagy-a new target of bone disease. Biomolecules 12(10):1420
  65. Mobasheri A, Rayman MP, Gualillo O, Sellam J, van der Kraan P, Fearon U (2017) The role of metabolism in the pathogenesis of osteoarthritis. Nat Rev Rheumatol 13:302���311 [PMID: 28381830]
  66. Bouderlique T, Vuppalapati KK, Newton PT, Li L, Barenius B, Chagin AS (2016) Targeted deletion of Atg5 in chondrocytes promotes age-related osteoarthritis. Ann Rheum Dis 75:627���631 [PMID: 26438374]
  67. Hwang HS, Kim HA (2015) Chondrocyte apoptosis in the pathogenesis of osteoarthritis. Int J Mol Sci 16:26035���26054 [PMID: 26528972]
  68. Salucci S, Falcieri E, Battistelli M (2022) Chondrocyte death involvement in osteoarthritis. Cell Tissue Res 389:159���170 [PMID: 35614364]
  69. Almonte-Becerril M, Navarro-Garcia F, Gonzalez-Robles A, Vega-Lopez MA, Lavalle C, Kouri JB (2010) Cell death of chondrocytes is a combination between apoptosis and autophagy during the pathogenesis of osteoarthritis within an experimental model. Apoptosis Int J Progr Cell Death 15:631���638 [DOI: 10.1007/s10495-010-0458-z]
  70. Sasaki H, Takayama K, Matsushita T, Ishida K, Kubo S, Matsumoto T et al (2012) Autophagy modulates osteoarthritis-related gene expression in human chondrocytes. Arthritis Rheum 64:1920���1928 [PMID: 22147463]
  71. Caram��s B, Taniguchi N, Seino D, Blanco FJ, D���Lima D, Lotz M (2012) Mechanical injury suppresses autophagy regulators and pharmacologic activation of autophagy results in chondroprotection. Arthritis Rheum 64:1182���1192 [PMID: 22034068]
  72. Vinatier C, Dom��nguez E, Guicheux J, Caram��s B (2018) Role of the inflammation-autophagy-senescence integrative network in osteoarthritis. Front Physiol 9:706 [PMID: 29988615]
  73. L��pez de Figueroa P, Lotz MK, Blanco FJ, Caram��s B (2015) Autophagy activation and protection from mitochondrial dysfunction in human chondrocytes. Arthritis Rheumatol (Hoboken, NJ) 67:966���76 [DOI: 10.1002/art.39025]
  74. Onishi M, Yamano K, Sato M, Matsuda N, Okamoto K (2021) Molecular mechanisms and physiological functions of mitophagy. EMBO J 40:e104705 [PMID: 33438778]
  75. Chen J, Long F (2018) mTOR signaling in skeletal development and disease. Bone research 6:1 [PMID: 29423330]
  76. Kim YC, Guan KL (2015) mTOR: a pharmacologic target for autophagy regulation. J Clin Investig 125:25���32 [PMID: 25654547]
  77. Kakiuchi Y, Yurube T, Kakutani K, Takada T, Ito M, Takeoka Y et al (2019) Pharmacological inhibition of mTORC1 but not mTORC2 protects against human disc cellular apoptosis, senescence, and extracellular matrix catabolism through Akt and autophagy induction. Osteoarthritis Cartilage 27:965���976 [PMID: 30716534]
  78. Tang F, Wang Y, Hemmings BA, R��egg C, Xue G (2018) PKB/Akt-dependent regulation of inflammation in cancer. Semin Cancer Biol 48:62���69 [PMID: 28476657]
  79. Fisch KM, Gamini R, Alvarez-Garcia O, Akagi R, Saito M, Muramatsu Y et al (2018) Identification of transcription factors responsible for dysregulated networks in human osteoarthritis cartilage by global gene expression analysis. Osteoarthritis Cartilage 26:1531���1538 [PMID: 30081074]
  80. Dalle Pezze P, Ruf S, Sonntag AG, Langelaar-Makkinje M, Hall P, Heberle AM et al (2016) A systems study reveals concurrent activation of AMPK and mTOR by amino acids. Nat Commun 7:13254 [PMID: 27869123]
  81. Zhang Y, Vasheghani F, Li YH, Blati M, Simeone K, Fahmi H et al (2015) Cartilage-specific deletion of mTOR upregulates autophagy and protects mice from osteoarthritis. Ann Rheum Dis 74:1432���1440 [PMID: 24651621]
  82. Hui W, Young DA, Rowan AD, Xu X, Cawston TE, Proctor CJ (2016) Oxidative changes and signalling pathways are pivotal in initiating age-related changes in articular cartilage. Ann Rheum Dis 75:449���458 [PMID: 25475114]
  83. Song B, Song H, Wang W, Wang H, Peng H, Cui J et al (2017) Beclin 1 overexpression inhibits chondrocyte apoptosis and downregulates extracellular matrix metabolism in osteoarthritis. Mol Med Rep 16:3958���3964 [PMID: 28731147]
  84. Tabibzadeh S (2021) Signaling pathways and effectors of aging. Front Biosci (Landmark edition) 26:50���96 [DOI: 10.2741/4889]
  85. Abrahamsen H, Stenmark H, Platta HW (2012) Ubiquitination and phosphorylation of Beclin 1 and its binding partners: tuning class III phosphatidylinositol 3-kinase activity and tumor suppression. FEBS Lett 586:1584���1591 [PMID: 22673570]
  86. Bohensky J, Leshinsky S, Srinivas V, Shapiro IM (2010) Chondrocyte autophagy is stimulated by HIF-1 dependent AMPK activation and mTOR suppression. Pediatr Nephrol (Berlin, Germany) 25:633���642 [DOI: 10.1007/s00467-009-1310-y]
  87. Alvarez-Garcia O, Matsuzaki T, Olmer M, Plate L, Kelly JW, Lotz MK (2017) Regulated in Development and DNA damage response 1 deficiency impairs autophagy and mitochondrial biogenesis in articular cartilage and increases the severity of experimental osteoarthritis. Arthritis Rheumatol (Hoboken, NJ) 69:1418���1428 [DOI: 10.1002/art.40104]
  88. Zeng CY, Wang XF, Hua FZ (2022) HIF-1�� in osteoarthritis: from pathogenesis to therapeutic implications. Front Pharmacol 13:927126 [PMID: 35865944]
  89. Hu S, Zhang C, Ni L, Huang C, Chen D, Shi K et al (2020) Stabilization of HIF-1�� alleviates osteoarthritis via enhancing mitophagy. Cell Death Dis 11:481 [PMID: 32587244]
  90. Li Y, Chen Y (2019) AMPK and autophagy. Adv Exp Med Biol 1206:85���108 [PMID: 31776981]
  91. Inoki K, Zhu T, Guan KL (2003) TSC2 mediates cellular energy response to control cell growth and survival. Cell 115:577���590 [PMID: 14651849]
  92. Zachari M, Ganley IG (2017) The mammalian ULK1 complex and autophagy initiation. Essays Biochem 61:585���596 [PMID: 29233870]
  93. Kim J, Kundu M, Viollet B, Guan KL (2011) AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 13:132���141 [PMID: 21258367]
  94. Salminen A, Kaarniranta K, Kauppinen A (2016) Age-related changes in AMPK activation: role for AMPK phosphatases and inhibitory phosphorylation by upstream signaling pathways. Ageing Res Rev 28:15���26 [PMID: 27060201]
  95. Lee IH, Cao L, Mostoslavsky R, Lombard DB, Liu J, Bruns NE et al (2008) A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy. Proc Natl Acad Sci USA 105:3374���3379 [PMID: 18296641]
  96. Meng J, Du H, Lv H, Lu J, Li J, Yao J (2022) Identification of the osteoarthritis signature gene PDK1 by machine learning and its regulatory mechanisms on chondrocyte autophagy and apoptosis. Front Immunol 13:1072526 [PMID: 36685513]
  97. Bamodu OA, Chang HL, Ong JR, Lee WH, Yeh CT, Tsai JT (2020) Elevated PDK1 expression drives PI3K/AKT/MTORsignaling promotes radiation-resistant and dedifferentiated phenotype of hepatocellular carcinoma. Cells 9(3):746
  98. Feng R, Zhang X, Yin J, Zhang Y, Ma Y, Zhang X et al (2021) A comprehensive study of the metabolism of flavonoid oroxin B in vivo and in vitro by UHPLC-Q-TOF-MS/MS. J Pharm Biomed Anal 197:113905 [PMID: 33636644]
  99. Lu R, He Z, Zhang W, Wang Y, Cheng P, Lv Z et al (2022) Oroxin B alleviates osteoarthritis through anti-inflammation and inhibition of PI3K/AKT/mTOR signaling pathway and enhancement of autophagy. Front Endocrinol 13:1060721 [DOI: 10.3389/fendo.2022.1060721]
  100. Chen Y, Pan X, Zhao J, Li C, Lin Y, Wang Y et al (2022) Icariin alleviates osteoarthritis through PI3K/Akt/mTOR/ULK1 signaling pathway. Eur J Med Res 27:204 [PMID: 36253872]
  101. Tang Y, Li Y, Xin D, Chen L, Xiong Z, Yu X (2021) Icariin alleviates osteoarthritis by regulating autophagy of chondrocytes by mediating PI3K/AKT/mTOR signaling. Bioengineered 12:2984���2999 [PMID: 34167449]
  102. Han H, Chen M, Li Z, Zhou S, Wu Y, Wei J (2022) Corosolic acid protects rat chondrocytes against IL-1��-induced ECM degradation by activating autophagy via PI3K/AKT/mTOR pathway and ameliorates rat osteoarthritis. Drug Des Dev Ther 16:2627���2637 [DOI: 10.2147/DDDT.S365279]
  103. Ni B, Pei W, Qu Y, Zhang R, Chu X, Wang Y, Huang X, You H (2021) MCC950, the NLRP3 inhibitor, protects against cartilage degradation in a mouse model of osteoarthritis. Oxid Med Cell Longev 2021:4139048. https://doi.org/10.1155/2021/4139048.PMID:34777685;PMCID:PMC8580635 [DOI: 10.1155/2021/4139048.PMID]
  104. Fu H, Wang C, Yang D, Wei Z, Xu J, Hu Z, Zhang Y, Wang W, Yan R, Cai Q (2018) Curcumin regulates proliferation, autophagy, and apoptosis in gastric cancer cells by affecting PI3K and P53 signaling. J Cell Physiol 233(6):4634���4642. https://doi.org/10.1002/jcp.26190 . Epub 2018 Jan 15 PMID: 28926094 [DOI: 10.1002/jcp.26190]
  105. Li X, Feng K, Li J, Yu D, Fan Q, Tang T, Yao X, Wang X (2017) Curcumin inhibits apoptosis of chondrocytes through activation ERK1/2 signaling pathways induced autophagy. Nutrients 9(4):414. https://doi.org/10.3390/nu9040414.PMID:28430129;PMCID:PMC5409753 [DOI: 10.3390/nu9040414.PMID]
  106. Han G, Zhang Y, Li H (2021) The combination treatment of curcumin and probucol protects chondrocytes from TNF-�� induced inflammation by enhancing autophagy and reducing apoptosis via the PI3K-Akt-mTOR pathway. Oxid Med Cell Longev 2021:5558066. https://doi.org/10.1155/2021/5558066.PMID:34257809;PMCID:PMC8249126 [DOI: 10.1155/2021/5558066.PMID]
  107. Kong C, Wang C, Shi Y, Yan L, Xu J, Qi W (2020) Active vitamin D activates chondrocyte autophagy to reduce osteoarthritis via mediating the AMPK-mTOR signaling pathway. Biochem Cell Biol 98(3):434���442
  108. Ge Y, Zhou S, Li Y, Wang Z, Chen S, Xia T et al (2019) Estrogen prevents articular cartilage destruction in a mouse model of AMPK deficiency via ERK-mTOR pathway. Ann Transl Med 7:336 [PMID: 31475206]
  109. Wang C, Yao Z, Zhang Y, Yang Y, Liu J, Shi Y et al (2020) Metformin mitigates cartilage degradation by activating AMPK/SIRT1-mediated autophagy in a mouse osteoarthritis model. Front Pharmacol 11:1114 [PMID: 32792951]
  110. Song Y, Wu Z, Zhao P (2022) The effects of metformin in the treatment of osteoarthritis: current perspectives. Front Pharmacol 13:952560 [PMID: 36081941]
  111. Yang X, Jiang T, Wang Y, Guo L (2019) The role and mechanism of SIRT1 in resveratrol-regulated osteoblast autophagy in osteoporosis rats. Sci Rep 9(1):18424. https://doi.org/10.1038/s41598-019-44766-3.PMID:31804494;PMCID:PMC6895060 [DOI: 10.1038/s41598-019-44766-3.PMID]
  112. Liang C, Xing H, Wang C, Xu X, Hao Y, Qiu B (2022) Resveratrol protection against IL-1��-induced chondrocyte damage via the SIRT1/FOXO1 signaling pathway. J Orthop Surg Res 17:406 [PMID: 36064420]
  113. Cheng NT, Guo A, Meng H (2016) The protective role of autophagy in experimental osteoarthritis, and the therapeutic effects of Torin 1 on osteoarthritis by activating autophagy. BMC Musculoskelet Disord 17:150 [PMID: 27052304]
  114. Chen CH, Ho ML, Chang LH, Kang L, Lin YS, Lin SY et al (2018) Parathyroid hormone-(1���34) ameliorated knee osteoarthritis in rats via autophagy. J Appl Physiol (Bethesda, Md���: 1985) 124:1177���85 [DOI: 10.1152/japplphysiol.00871.2017]
  115. Hulsmans M, Geeraert B, Arnould T, Tsatsanis C, Holvoet P (2013) PPAR agonist-induced reduction of Mcp1 in atherosclerotic plaques of obese, insulin-resistant mice depends on adiponectin-induced Irak3 expression. PLoS ONE 8(4):e62253. https://doi.org/10.1371/journal.pone.0062253 . PMID:23620818; PMCID:PMC3631170 [DOI: 10.1371/journal.pone.0062253]
  116. Nogueira-Recalde U, Lorenzo-G��mez I, Blanco FJ, Loza MI, Grassi D, Shirinsky V et al (2019) Fibrates as drugs with senolytic and autophagic activity for osteoarthritis therapy. EBioMedicine 45:588���605 [PMID: 31285188]
  117. Jiang LB, Meng DH, Lee SM, Liu SH, Xu QT, Wang Y et al (2016) Dihydroartemisinin inhibits catabolism in rat chondrocytes by activating autophagy via inhibition of the NF-��B pathway. Sci Rep 6:38979 [PMID: 27941926]
  118. Hu W, Chen SS, Zhang JL, Lou XE, Zhou HJ (2014) Dihydroartemisinin induces autophagy by suppressing NF-��B activation. Cancer Lett 343(2):239���248. https://doi.org/10.1016/j.canlet.2013.09.035 . Epub 2013 Oct 4 PMID: 24099910 [DOI: 10.1016/j.canlet.2013.09.035]
  119. Sun K, Wu Y, Zeng Y, Xu J, Wu L, Li M et al (2022) The role of the sirtuin family in cartilage and osteoarthritis: molecular mechanisms and therapeutic targets. Arthritis Res Ther 24:286 [PMID: 36585687]
  120. Feng K, Ge Y, Chen Z, Li X, Liu Z, Li X et al (2019) Curcumin inhibits the PERK-eIF2��-CHOP pathway through promoting SIRT1 expression in oxidative stress-induced rat chondrocytes and ameliorates osteoarthritis progression in a rat model. Oxid Med Cell Longev 2019:8574386 [PMID: 31223428]
  121. Qiu L, Luo Y, Chen X (2018) Quercetin attenuates mitochondrial dysfunction and biogenesis via upregulated AMPK/SIRT1 signaling pathway in OA rats. Biomed Pharmacother 103:1585���91
  122. Wang C, Gao Y, Zhang Z, Chi Q, Liu Y, Yang L et al (2020) Safflower yellow alleviates osteoarthritis and prevents inflammation by inhibiting PGE2 release and regulating NF-��B/SIRT1/AMPK signaling pathways. Phytomed Int J Phytother Phytopharmacol 78:153305
  123. Wu WT, Chen YR, Lu DH, Senatov FS, Yang KC, Wang CC (2021) Silymarin modulates catabolic cytokine expression through Sirt1 and SOX9 in human articular chondrocytes. J Orthop Surg Res 16:147 [PMID: 33610183]
  124. Jiang C, Sun ZM, Hu JN, Jin Y, Guo Q, Xu JJ et al (2019) Cyanidin ameliorates the progression of osteoarthritis via the Sirt6/NF-��B axis in vitro and in vivo. Food Funct 10:5873���5885 [PMID: 31464310]
  125. Wang FS, Kuo CW, Ko JY, Chen YS, Wang SY, Ke HJ et al (2020) Irisin mitigates oxidative stress, chondrocyte dysfunction and osteoarthritis development through regulating mitochondrial integrity and autophagy. Antioxidants Basel, Switzerland 9(9):810
  126. Wang J, Wang K, Huang C, Lin D, Zhou Y, Wu Y et al (2018) SIRT3 Activation by dihydromyricetin suppresses chondrocytes degeneration via maintaining mitochondrial homeostasis. Int J Biol Sci 14:1873���1882 [PMID: 30443190]
  127. D���Adamo S, Cetrullo S, Guidotti S, Borz�� RM, Flamigni F (2017) Hydroxytyrosol modulates the levels of microRNA-9 and its target sirtuin-1 thereby counteracting oxidative stress-induced chondrocyte death. Osteoarthritis Cartilage 25:600���610 [PMID: 27914878]
  128. Zhi LQ, Yao SX, Liu HL, Li M, Duan N, Ma JB (2018) Hydroxytyrosol inhibits the inflammatory response of osteoarthritis chondrocytes via SIRT6-mediated autophagy. Mol Med Rep 17:4035���4042 [PMID: 29286133]
  129. Liu L, Zhang W, Liu T, Tan Y, Chen C, Zhao J et al (2023) The physiological metabolite ��-ketoglutarate ameliorates osteoarthritis by regulating mitophagy and oxidative stress. Redox Biol 62:102663 [PMID: 36924682]
  130. D���Amico D, Olmer M, Fouassier AM, Vald��s P, Andreux PA, Rinsch C et al (2022) Urolithin A improves mitochondrial health, reduces cartilage degeneration, and alleviates pain in osteoarthritis. Aging Cell 21:e13662 [PMID: 35778837]
  131. Jin Z, Chang B, Wei Y, Yang Y, Zhang H, Liu J et al (2022) Curcumin exerts chondroprotective effects against osteoarthritis by promoting AMPK/PINK1/Parkin-mediated mitophagy. Biomed Pharmacother 151:113092
  132. Tang Q, Zheng G, Feng Z, Chen Y, Lou Y, Wang C et al (2017) Trehalose ameliorates oxidative stress-mediated mitochondrial dysfunction and ER stress via selective autophagy stimulation and autophagic flux restoration in osteoarthritis development. Cell Death Dis 8:e3081 [PMID: 28981117]
  133. Li J, Jiang M, Yu Z, Xiong C, Pan J, Cai Z, Xu N, Zhou X, Huang Y, Yang Z (2022) Artemisinin relieves osteoarthritis by activating mitochondrial autophagy through reducing TNFSF11 expression and inhibiting PI3K/AKT/mTOR signaling in cartilage. Cell Mol Biol Lett 27(1):62. https://doi.org/10.1186/s11658-022-00365-1.PMID:35902802;PMCID:PMC9331798 [DOI: 10.1186/s11658-022-00365-1.PMID]
  134. Jia X, Ma J, Chen X, Li W, Zhou X, Lei B et al (2022) Immunoregulation and anti-metalloproteinase bioactive injectable polysalicylate matrixgel for efficiently treating osteoarthritis. Materials Today Bio 15:100277 [PMID: 35601894]
  135. Kooshki L, Mahdavi P, Fakhri S, Akkol EK, Khan H (2022) Targeting lactate metabolism and glycolytic pathways in the tumor microenvironment by natural products: a promising strategy in combating cancer. BioFactors (Oxford, England) 48:359���383 [PMID: 34724274]
  136. Tan C, Li L, Han J, Xu K, Liu X (2022) A new strategy for osteoarthritis therapy: inhibition of glycolysis. Front Pharmacol 13:1057229 [PMID: 36438808]
  137. Chen P, Liu X, Gu C, Zhong P, Song N, Li M et al (2022) A plant-derived natural photosynthetic system for improving cell anabolism. Nature 612:546���554 [PMID: 36477541]
  138. Yang Z, Li W, Song C, Leng H (2022) CTGF as a multifunctional molecule for cartilage and a potential drug for osteoarthritis. Front Endocrinol 13:1040526 [DOI: 10.3389/fendo.2022.1040526]
  139. Velasco-Salgado C, Pontes-Quero GM, Garc��a-Fern��ndez L, Aguilar MR, de Wit K, V��zquez-Lasa B et al (2022) The role of polymeric biomaterials in the treatment of articular osteoarthritis. Pharmaceutics 14(8):1644
  140. Brown S, Kumar S, Sharma B (2019) Intra-articular targeting of nanomaterials for the treatment of osteoarthritis. Acta Biomater 93:239���257 [PMID: 30862551]
  141. Zhang X, Shi Y, Zhang Z, Yang Z, Huang G (2018) Intra-articular delivery of tetramethylpyrazine microspheres with enhanced articular cavity retention for treating osteoarthritis. Asian J Pharm Sci 13:229���238 [PMID: 32104396]
  142. Kou L, Xiao S, Sun R, Bao S, Yao Q, Chen R (2019) Biomaterial-engineered intra-articular drug delivery systems for osteoarthritis therapy. Drug Deliv 26:870���885 [PMID: 31524006]
  143. Xue S, Zhou X, Sang W, Wang C, Lu H, Xu Y et al (2021) Cartilage-targeting peptide-modified dual-drug delivery nanoplatform with NIR laser response for osteoarthritis therapy. Bioactive Mater 6:2372���2389 [DOI: 10.1016/j.bioactmat.2021.01.017]
  144. Huang H, Lou Z, Zheng S, Wu J, Yao Q, Chen R et al (2022) Intra-articular drug delivery systems for osteoarthritis therapy: shifting from sustained release to enhancing penetration into cartilage. Drug Deliv 29:767���791 [PMID: 35261301]
  145. Ni Z, Kuang L, Chen H, Xie Y, Zhang B, Ouyang J et al (2019) The exosome-like vesicles from osteoarthritic chondrocyte enhanced mature IL-1�� production of macrophages and aggravated synovitis in osteoarthritis. Cell Death Dis 10:522 [PMID: 31285423]
  146. Wu Y, Li J, Zeng Y, Pu W, Mu X, Sun K et al (2022) Exosomes rewire the cartilage microenvironment in osteoarthritis: from intercellular communication to therapeutic strategies. Int J Oral Sci 14:40 [PMID: 35927232]
  147. Yang L, Tan JY, Ma H, Zhao H, Lai J, Chen JX et al (2018) Warm-needle moxibustion for spasticity after stroke: a systematic review of randomized controlled trials. Int J Nurs Stud 82:129���138 [PMID: 29631145]
  148. Ye JN, Su CG, Jiang YQ, Zhou Y, Sun WX, Zheng XX et al (2022) Effects of acupuncture on cartilage p38MAPK and mitochondrial pathways in animal model of knee osteoarthritis: a systematic evaluation and meta-analysis. Front Neurosci 16:1098311 [PMID: 36711149]
  149. Jun JH, Choi TY, Robinson N, Park JY, Jun EY, Kim KH et al (2022) Warm needle acupuncture for osteoarthritis: a systematic review and meta-analysis. Phytomed Int J Phytother Phytopharmacol 106:154388

MeSH Term

Chondrocytes
Humans
Osteoarthritis
Autophagy
Animals
Cartilage, Articular
Signal Transduction
Biomarkers
Apoptosis

Chemicals

Biomarkers
Journal Article Review

Word Cloud

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