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Abstract
Background: Osteoarthritis (OA) is a common joint disease, and existing drugs cannot cure OA, so there is an urgent need to identify new targets. Mitophagy plays an important role in OA; however, the role of mitophagy in the OA immune system is not yet clear.
Methods: In this study, differential analysis and enrichment analysis were used to identify mitophagy-related genes (MRGs) with differential expression in OA and the functional pathways involved in OA. Subsequently, two machine learning methods, RF and LASSO, were used to screen MRGs with diagnostic value and construct nomograms. At the same time, the relationship between mitophagy and OA immune response was explored by immunoinfiltration analysis.
Results: Forty-three differentially MRGs were identified in OA, of which six MRGs (GABARAPL2, PARL, GABARAPL1, JUN, RRAS, and SNX7) were associated with the diagnosis of OA. The ROC analysis results show that these 6 MRGs have high predictive accuracy in the diagnosis of OA. In immune infiltration analysis, we found that the abundance of significantly different immune cells in OA was mostly upregulated. In addition, the expression of diagnostic-related MRGs is correlated with changes in the abundance of immune cells in OA.
Conclusion: This study demonstrates that six MRGs can be used as diagnostic biomarkers. The expression of diagnostic-related MRGs is correlated with changes in the abundance of immune cells in OA. At the same time, mitophagy may affect the immune microenvironment of OA by regulating immune cells, ultimately leading to the progression of OA.
Keywords
diagnosis
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immune cell infiltration
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machine learning
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mitophagy
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osteoarthritis (OA)
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quantitative real-time polymerase chain reaction (qPCR)
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Shiqiang Ruan, Dongxu Tang, Yanfei Luo, Hao Song.
Identification of mitophagy-related biomarkers in osteoarthritis.
Animal Models and Experimental Medicine, 2024, 7(6): 781-792 DOI:10.1002/ame2.12416
| [1] |
YaoQ, WuX, TaoC, et al. Osteoarthritis: pathogenic signaling pathways and therapeutic targets. Signal Transduct Target Ther. 2023;8(1):56.
|
| [2] |
YunusMHM, NordinA, KamalH. Pathophysiological perspective of osteoarthritis. Medicina (Kaunas). 2020;56(11):614.
|
| [3] |
Martel-PelletierJ, Barr AJ, CicuttiniFM, et al. Osteoarthritis. Nat Rev Dis Primers. 2016;2:16072.
|
| [4] |
Taruc-UyRL, LynchSA. Diagnosis and treatment of osteoarthritis. Prim Care. 2013;40(4):821-836, vii.
|
| [5] |
LiangY, LinF, HuangY. Identification of biomarkers associated with diagnosis of osteoarthritis patients based on bioinformatics and machine learning. J Immunol Res. 2022;2022:5600190.
|
| [6] |
XiaB, ChenD, ZhangJ, Hu S, JinH, TongP. Osteoarthritis pathogenesis: a review of molecular mechanisms. Calcif Tissue Int. 2014;95(6):495-505.
|
| [7] |
ZengZ, ZhouX, WangY, et al. Mitophagy-a new target of bone disease. Biomol Ther. 2022;12(10):1420.
|
| [8] |
WangS, DengZ, MaY, et al. The role of autophagy and mitophagy in bone metabolic disorders. Int J Biol Sci. 2020;16(14):2675-2691.
|
| [9] |
MaruottiN, Corrado A, CantatoreFP. Osteoblast role in osteoarthritis pathogenesis. J Cell Physiol. 2017;232(11):2957-2963.
|
| [10] |
ShinHJ, ParkH, ShinN, et al. Pink1-mediated Chondrocytic mitophagy contributes to cartilage degeneration in osteoarthritis. J Clin Med. 2019;8(11):1849.
|
| [11] |
HuS, ZhangC, NiL, et al. Stabilization of HIF-1α alleviates osteoarthritis via enhancing mitophagy. Cell Death Dis. 2020;11(6):481.
|
| [12] |
SunK, JingX, GuoJ, YaoX, GuoF. Mitophagy in degenerative joint diseases. Autophagy. 2021;17(9):2082-2092.
|
| [13] |
LiuL, ZhangW, LiuT, et al. The physiological metabolite α-ketoglutarate ameliorates osteoarthritis by regulating mitophagy and oxidative stress. Redox Biol. 2023;62:102663.
|
| [14] |
CaoH, ZhouX, XuB, et al. Advances in the study of mitophagy in osteoarthritis. J Zhejiang Univ Sci B. 2024;25(3):197-211.
|
| [15] |
LopesEBP, Filiberti A, HusainSA, HumphreyMB. Immune Contributions to osteoarthritis. Curr Osteoporos Rep. 2017;15(6):593-600.
|
| [16] |
KandahariAM, YangX, DigheAS, Pan D, CuiQ. Recognition of immune response for the early diagnosis and treatment of osteoarthritis. J Immunol Res. 2015;2015:192415.
|
| [17] |
GkikasI, Palikaras K, TavernarakisN. The role of mitophagy in innate immunity. Front Immunol. 2018;9:1283.
|
| [18] |
YangYY, GaoZX, MaoZH, Liu DW, LiuZS, WuP. Identification of ULK1 as a novel mitophagy-related gene in diabetic nephropathy. Front Endocrinol (Lausanne). 2023;13:1079465.
|
| [19] |
TschonM, Veronesi F, GianniniS, FiniM. Fresh osteochondral allotransplants: outcomes, failures and future developments. Injury. 2017;48(7):1287-1295.
|
| [20] |
HwangHS, KimHA. Chondrocyte apoptosis in the pathogenesis of osteoarthritis. Int J Mol Sci. 2015;16(11):26035-26054.
|
| [21] |
ZhouQ, RenQ, JiaoL, et al. The potential roles of JAK/STAT signaling in the progression of osteoarthritis. Front Endocrinol (Lausanne). 2022;13:1069057.
|
| [22] |
LuJ, ZhangH, PanJ, et al. Fargesin ameliorates osteoarthritis via macrophage reprogramming by downregulating MAPK and NF-κB pathways. Arthritis Res Ther. 2021;23(1):142.
|
| [23] |
JinZ, ChangB, WeiY, et al. Curcumin exerts chondroprotective effects against osteoarthritis by promoting AMPK/PINK1/parkin-mediated mitophagy. Biomed Pharmacother. 2022;151:113092.
|
| [24] |
NingP, JiangX, YangJ, Zhang J, YangF, CaoH. Mitophagy: a potential therapeutic target for insulin resistance. Front Physiol. 2022;13:957968.
|
| [25] |
HarperJW, Ordureau A, HeoJM. Building and decoding ubiquitin chains for mitophagy. Nat Rev Mol Cell Biol. 2018;19(2):93-108.
|
| [26] |
Woodell-MayJE, Sommerfeld SD. Role of inflammation and the immune system in the progression of osteoarthritis. J Orthop Res. 2020;38(2):253-257.
|
| [27] |
ZupanJ, JerasM, MarcJ. Osteoimmunology and the influence of pro-inflammatory cytokines on osteoclasts. Biochem Med (Zagreb). 2013;23(1):43-63.
|
| [28] |
ZhuY, MassenS, TerenzioM, et al. Modulation of serines 17 and 24 in the LC3-interacting region of Bnip3 determines pro-survival mitophagy versus apoptosis. J Biol Chem. 2013;288(2):1099-1113.
|
| [29] |
LepetsosP, Papavassiliou KA, PapavassiliouAG. Redox and NF-κB signaling in osteoarthritis. Free Radic Biol Med. 2019;132:90-100.
|
| [30] |
ZhangH, SunH, ZhangW, Xu Y, GengD. Identification of key genes and potential mechanisms based on the autophagy regulatory network in osteoclasts using a murine osteoarthritis model. J Inflamm Res. 2022;15:2333-2347.
|
| [31] |
ChakramaFZ, Seguin-Py S, Le GrandJN, et al. GABARAPL1 (GEC1) associates with autophagic vesicles. Autophagy. 2010;6(4):495-505.
|
| [32] |
ChengNT, MengH, MaLF, et al. Role of autophagy in the progression of osteoarthritis: the autophagy inhibitor, 3-methyladenine, aggravates the severity of experimental osteoarthritis. Int J Mol Med. 2017;39(5):1224-1232.
|
| [33] |
GreeneAW, Grenier K, AguiletaMA, et al. Mitochondrial processing peptidase regulates PINK1 processing, import and parkin recruitment. EMBO Rep. 2012;13(4):378-385.
|
| [34] |
RahmanFA, Quadrilatero J. Mitochondrial network remodeling: an important feature of myogenesis and skeletal muscle regeneration. Cell Mol Life Sci. 2021;78(10):4653-4675.
|
| [35] |
RheeJ, ParkSH, KimSK, et al. Inhibition of BATF/JUN transcriptional activity protects against osteoarthritic cartilage destruction. Ann Rheum Dis. 2017;76(2):427-434.
|
| [36] |
Ada-NguemaAS, XeniasH, HofmanJM, Wiggins CH, SheetzMP, KeelyPJ. The small GTPase R-Ras regulates organization of Actin and drives membrane protrusions through the activity of PLCepsilon. J Cell Sci. 2006;119(Pt 7):1307-1319.
|
| [37] |
LehtoM, Mäyränpää MI, PellinenT, et al. The R-Ras interaction partner ORP3 regulates cell adhesion. J Cell Sci. 2008;121(Pt 5):695-705.
|
| [38] |
WangYH, TsaiCH, LiuSC, et al. miR-150-5p and XIST interaction controls monocyte adherence: implications for osteoarthritis therapy. Front Immunol. 2022;13:1004334.
|
| [39] |
AntónZ, BetinVMS, SimonettiB, et al. A heterodimeric SNX4–SNX7 SNX-BAR autophagy complex coordinates ATG9A trafficking for efficient autophagosome assembly. J Cell Sci. 2020;133(14):jcs246306.
|
| [40] |
YanJ, ShenM, SuiB, et al. Autophagic LC3+ calcified extracellular vesicles initiate cartilage calcification in osteoarthritis. Sci Adv. 2022;8(19):eabn1556.
|
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2024 The Authors. Animal Models and Experimental Medicine published by John Wiley & Sons Australia, Ltd on behalf of The Chinese Association for Laboratory Animal Sciences.