nach oben

Erschienen in:

09.01.2021 | Original Article

Identification of abnormally methylated–differentially expressed genes and pathways in osteoarthritis: a comprehensive bioinformatic study

verfasst von: Linli Zheng, Weishen Chen, Guoyan Xian, Baiqi Pan, Yongyu Ye, Minghui Gu, Yinyue Ma, Ziji Zhang, Puyi Sheng

Erschienen in: Clinical Rheumatology | Ausgabe 8/2021

Einloggen, um Zugang zu erhalten

Abstract

Objectives

To investigate abnormally methylated–differentially expressed genes (DEGs) and their related pathways in osteoarthritis (OA) by comprehensive bioinformatic analysis.

Methods

Gene expression profiles of GSE51588 and GSE114007, and a gene methylation microarray data GSE63695 were downloaded from the Gene Expression Omnibus (GEO) repository. Abnormally methylated DEGs were identified. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of these genes were subsequently performed using the Database for Annotation, Visualization and Integrated Discovery (DAVID). The protein-protein interaction (PPI) network was built from STRING. Module analysis and hub gene identification were performed by using Cytoscape. Co-expression analysis was also constructed using the CEMiTool package.

Results

In total, 133 abnormally methylated DEGs were identified, including 85 hypomethylation high-expression genes and 48 hypermethylation low-expression genes. Among biological processes and KEGG pathways of abnormally methylated DEGs, collagen fibril organization was enriched most frequently, and pathways of oxidative stress and aging were enriched, including HIF-1 signaling pathway, AMPK signaling pathway, and FoxO signaling pathway. In PPI networks, the hub genes of hypomethylation high-expression genes were COL1A1, COL3A1, COL1A2, COL5A2, LUM, MMP2, SPARC, COL2A1, COL6A2, and COL7A1, and the hub genes of hypermethylation low-expression genes were VEGFA, SLC2A1, LDHA, PDK1, and BNIP3. Combined with co-expression analysis, COL3A1, LUM, and MMP2 were the critical hypomethylation high-expression hub genes in medial tibia subchondral bone.

Conclusions

Our study implied abnormally methylated DEGs and dysregulated pathways in OA. Common methylation biomarkers included COL3A1, LUM, and MMP2, and we also found that THBS2 may serve as a novel biomarker in end-stage OA.

Key Points

• Abnormally methylated differentially expressed genes regulate osteoarthritis.

• Hypomethylation high-expression genes were related to the extracellular matrix.

• Hypermethylation low-expression genes were related to oxidative stress and aging.

• COL3A1, LUM, and MMP2 were potential methylation biomarkers for osteoarthritis.

Nur mit Berechtigung zugänglich

Rice SJ, Beier F, Young DA, Loughlin J (2020) Interplay between genetics and epigenetics in osteoarthritis. Nat Rev Rheumatol 16:268–281. https://doi.org/10.1038/s41584-020-0407-3CrossRefPubMed

Hunter DJ, Bierma-Zeinstra S (2019) Osteoarthritis. Lancet 393:1745–1759. https://doi.org/10.1016/s0140-6736(19)30417-9CrossRefPubMed

Martel-Pelletier J, Barr AJ, Cicuttini FM, Conaghan PG, Cooper C, Goldring MB, Goldring SR, Jones G, Teichtahl AJ, Pelletier J-P (2016) Osteoarthritis. Nature Rev Dis Primers 2:16072. https://doi.org/10.1038/nrdp.2016.72CrossRef

Schulze-Tanzil G (2019) Intraarticular ligament degeneration is interrelated with cartilage and bone destruction in osteoarthritis. Cells 8:990. https://doi.org/10.3390/cells8090990CrossRefPubMedCentral

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. https://doi.org/10.1038/nrrheum.2017.50CrossRefPubMed

Jeon OH, Kim C, Laberge R-M, Demaria M, Rathod S, Vasserot AP, Chung JW, Kim DH, Poon Y, David N, Baker DJ, van Deursen JM, Campisi J, Elisseeff JH (2017) Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nat Med 23:775–781. https://doi.org/10.1038/nm.4324CrossRefPubMedPubMedCentral

Miranda-Duarte A (2018) DNA methylation in osteoarthritis: current status and therapeutic implications. Open Rheumatol J 12:37–49. https://doi.org/10.2174/1874312901812010037CrossRefPubMedPubMedCentral

Kuttapitiya A, Assi L, Laing K, Hing C, Mitchell P, Whitley G, Harrison A, Howe FA, Ejindu V, Heron C, Sofat N (2017) Microarray analysis of bone marrow lesions in osteoarthritis demonstrates upregulation of genes implicated in osteochondral turnover, neurogenesis and inflammation. Ann Rheum Dis 76:1764–1773. https://doi.org/10.1136/annrheumdis-2017-211396CrossRefPubMed

Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, Smyth GK (2015) limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res 43:e47. https://doi.org/10.1093/nar/gkv007CrossRefPubMedPubMedCentral

10.

Aryee MJ, Jaffe AE, Corrada-Bravo H, Ladd-Acosta C, Feinberg AP, Hansen KD, Irizarry RA (2014) Minfi: a flexible and comprehensive Bioconductor package for the analysis of Infinium DNA methylation microarrays. Bioinformatics (Oxford, England) 30:1363–1369. https://doi.org/10.1093/bioinformatics/btu049CrossRef

11.

Pidsley R, Wong CCY, Volta M, Lunnon K, Mill J, Schalkwyk LC (2013) A data-driven approach to preprocessing Illumina 450K methylation array data. BMC Genomics 14:293. https://doi.org/10.1186/1471-2164-14-293CrossRefPubMedPubMedCentral

12.

Dennis G Jr, Sherman BT, Hosack DA, Yang J, Gao W, Lane HC, Lempicki RA (2003) DAVID: database for annotation, visualization, and integrated discovery. Genome Biol 4:P3CrossRef

13.

Szklarczyk D, Gable AL, Lyon D, Junge A, Wyder S, Huerta-Cepas J, Simonovic M, Doncheva NT, Morris JH, Bork P, Jensen LJ, Mering CV (2019) STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res 47:D607–d613. https://doi.org/10.1093/nar/gky1131CrossRefPubMed

14.

Russo PST, Ferreira GR, Cardozo LE, Bürger MC, Arias-Carrasco R, Maruyama SR, Hirata TDC, Lima DS, Passos FM, Fukutani KF, Lever M, Silva JS, Maracaja-Coutinho V, Nakaya HI (2018) CEMiTool: a Bioconductor package for performing comprehensive modular co-expression analyses. BMC Bioinformatics 19:56. https://doi.org/10.1186/s12859-018-2053-1CrossRefPubMedPubMedCentral

15.

Felka T, Rothdiener M, Bast S, Uynuk-Ool T, Zouhair S, Ochs BG, De Zwart P, Stoeckle U, Aicher WK, Hart ML, Shiozawa T, Grodzinsky AJ, Schenke-Layland K, Venkatesan JK, Cucchiarini M, Madry H, Kurz B, Rolauffs B (2016) Loss of spatial organization and destruction of the pericellular matrix in early osteoarthritis in vivo and in a novel in vitro methodology. Osteoarthr Cartil 24:1200–1209. https://doi.org/10.1016/j.joca.2016.02.001CrossRef

16.

Sun K, Luo J, Guo J, Yao X, Jing X, Guo F (2020) The PI3K/AKT/mTOR signaling pathway in osteoarthritis: a narrative review. Osteoarthr Cartil 28:400–409. https://doi.org/10.1016/j.joca.2020.02.027CrossRef

17.

Xue JF, Shi ZM, Zou J, Li XL (2017) Inhibition of PI3K/AKT/mTOR signaling pathway promotes autophagy of articular chondrocytes and attenuates inflammatory response in rats with osteoarthritis. Biomed Pharmacother 89:1252–1261. https://doi.org/10.1016/j.biopha.2017.01.130CrossRefPubMed

18.

Dai M, Sui B, Xue Y, Liu X, Sun J (2018) Cartilage repair in degenerative osteoarthritis mediated by squid type II collagen via immunomodulating activation of M2 macrophages, inhibiting apoptosis and hypertrophy of chondrocytes. Biomaterials 180:91–103. https://doi.org/10.1016/j.biomaterials.2018.07.011CrossRefPubMed

19.

Steinberg J, Ritchie GRS, Roumeliotis TI, Jayasuriya RL, Clark MJ, Brooks RA, Binch ALA, Shah KM, Coyle R, Pardo M, Le Maitre CL, Ramos YFM, Nelissen R, Meulenbelt I, McCaskie AW, Choudhary JS, Wilkinson JM, Zeggini E (2017) Integrative epigenomics, transcriptomics and proteomics of patient chondrocytes reveal genes and pathways involved in osteoarthritis. Sci Rep 7:8935. https://doi.org/10.1038/s41598-017-09335-6CrossRefPubMedPubMedCentral

20.

Hosseininia S, Weis MA, Rai J, Kim L, Funk S, Dahlberg LE, Eyre DR (2016) Evidence for enhanced collagen type III deposition focally in the territorial matrix of osteoarthritic hip articular cartilage. Osteoarthr Cartil 24:1029–1035. https://doi.org/10.1016/j.joca.2016.01.001CrossRef

21.

Zelenski NA, Leddy HA, Sanchez-Adams J, Zhang J, Bonaldo P, Liedtke W, Guilak F (2015) Type VI collagen regulates pericellular matrix properties, chondrocyte swelling, and mechanotransduction in mouse articular cartilage. Arthritis Rheum 67:1286–1294. https://doi.org/10.1002/art.39034CrossRef

22.

Chou CH, Lee CH, Lu LS, Song IW, Chuang HP, Kuo SY, Wu JY, Chen YT, Kraus VB, Wu CC, Lee MT (2013) Direct assessment of articular cartilage and underlying subchondral bone reveals a progressive gene expression change in human osteoarthritic knees. Osteoarthr Cartil 21:450–461. https://doi.org/10.1016/j.joca.2012.11.016CrossRef

23.

Henrotin Y, Addison S, Kraus V, Deberg M (2007) Type II collagen markers in osteoarthritis: what do they indicate? Curr Opin Rheumatol 19:444–450. https://doi.org/10.1097/BOR.0b013e32829fb3b5CrossRefPubMed

24.

Kos K, Wilding JP (2010) SPARC: a key player in the pathologies associated with obesity and diabetes. Nat Rev Endocrinol 6:225–235. https://doi.org/10.1038/nrendo.2010.18CrossRefPubMed

25.

Nakamura S, Kamihagi K, Satakeda H, Katayama M, Pan H, Okamoto H, Noshiro M, Takahashi K, Yoshihara Y, Shimmei M, Okada Y, Kato Y (1996) Enhancement of SPARC (osteonectin) synthesis in arthritic cartilage. Increased levels in synovial fluids from patients with rheumatoid arthritis and regulation by growth factors and cytokines in chondrocyte cultures. Arthritis Rheum 39:539–551. https://doi.org/10.1002/art.1780390402CrossRefPubMed

26.

Zeng GQ, Chen AB, Li W, Song JH, Gao CY (2015) High MMP-1, MMP-2, and MMP-9 protein levels in osteoarthristis. Genet Mol Res 4:14811–14822. https://doi.org/10.4238/2015.November.18.46CrossRef

27.

Shu CC, Flannery CR, Little CB, Melrose J (2019) Catabolism of fibromodulin in developmental rudiment and pathologic articular cartilage demonstrates novel roles for MMP-13 and ADAMTS-4 in C-terminal processing of SLRPs. Int J Mol Sci 20. https://doi.org/10.3390/ijms20030579

28.

Barreto G, Senturk B, Colombo L, Brück O, Neidenbach P, Salzmann G, Zenobi-Wong M, Rottmar M (2020) Lumican is upregulated in osteoarthritis and contributes to TLR4-induced pro-inflammatory activation of cartilage degradation and macrophage polarization. Osteoarthr Cartil 28:92–101. https://doi.org/10.1016/j.joca.2019.10.011CrossRef

29.

Johnson K, Jung A, Murphy A, Andreyev A, Dykens J, Terkeltaub R (2000) Mitochondrial oxidative phosphorylation is a downstream regulator of nitric oxide effects on chondrocyte matrix synthesis and mineralization. Arthritis Rheum 43:1560–1570. https://doi.org/10.1002/1529-0131(200007)43:7<1560::Aid-anr21>3.0.Co;2-sCrossRefPubMed

30.

Bouaziz W, Sigaux J, Modrowski D, Devignes CS, Funck-Brentano T, Richette P, Ea HK, Provot S, Cohen-Solal M, Haÿ E (2016) Interaction of HIF1α and β-catenin inhibits matrix metalloproteinase 13 expression and prevents cartilage damage in mice. Proc Natl Acad Sci U S A 113:5453–5458. https://doi.org/10.1073/pnas.1514854113CrossRefPubMedPubMedCentral

31.

O’Neill LAJ, Hardie DG (2013) Metabolism of inflammation limited by AMPK and pseudo-starvation. Nature 493:346–355. https://doi.org/10.1038/nature11862CrossRefPubMed

32.

Terkeltaub R, Yang B, Lotz M, Liu-Bryan R (2011) Chondrocyte AMP-activated protein kinase activity suppresses matrix degradation responses to proinflammatory cytokines interleukin-1β and tumor necrosis factor α. Arthritis Rheum 63:1928–1937. https://doi.org/10.1002/art.30333CrossRefPubMedPubMedCentral

33.

van der Horst A, Burgering BM (2007) Stressing the role of FoxO proteins in lifespan and disease. Nat Rev Mol Cell Biol 8:440–450. https://doi.org/10.1038/nrm2190CrossRefPubMed

34.

Akasaki Y, Hasegawa A, Saito M, Asahara H, Iwamoto Y, Lotz MK (2014) Dysregulated FOXO transcription factors in articular cartilage in aging and osteoarthritis. Osteoarthr Cartil 22:162–170. https://doi.org/10.1016/j.joca.2013.11.004CrossRef

35.

Hamilton JL, Nagao M, Levine BR, Chen D, Olsen BR, Im HJ (2016) Targeting VEGF and its receptors for the treatment of osteoarthritis and associated pain. J Bone Miner Res 31:911–924. https://doi.org/10.1002/jbmr.2828CrossRefPubMed

36.

Nagai T, Sato M, Kobayashi M, Yokoyama M, Tani Y, Mochida J (2014) Bevacizumab, an anti-vascular endothelial growth factor antibody, inhibits osteoarthritis. Arthritis Res Ther 16:427. https://doi.org/10.1186/s13075-014-0427-yCrossRefPubMedPubMedCentral

37.

Mobasheri A, Dobson H, Mason SL, Cullingham F, Shakibaei M, Moley JF, Moley KH (2005) Expression of the GLUT1 and GLUT9 facilitative glucose transporters in embryonic chondroblasts and mature chondrocytes in ovine articular cartilage. Cell Biol Int 29:249–260. https://doi.org/10.1016/j.cellbi.2004.11.024CrossRefPubMed

38.

Ge Q, Wang H, Xu X, Xu L, Zhai L, Tao R (2017) PDK1 promotes apoptosis of chondrocytes via modulating MAPK pathway in osteoarthritis. Tissue Cell 49:719–725. https://doi.org/10.1016/j.tice.2017.10.004CrossRefPubMed

39.

Reed JC (1998) Bcl-2 family proteins. Oncogene 17:3225–3236. https://doi.org/10.1038/sj.onc.1202591CrossRefPubMed

40.

Veron V, Marandel L, Liu J, Vélez EJ, Lepais O, Panserat S, Skiba S, Seiliez I (2018) DNA methylation of the promoter region of bnip3 and bnip3l genes induced by metabolic programming. BMC Genomics 19:677. https://doi.org/10.1186/s12864-018-5048-4CrossRefPubMedPubMedCentral

41.

Rai MF, Sandell LJ, Barrack TN, Cai L, Tycksen ED, Tang SY, Silva MJ, Barrack RL (2018) A microarray study of articular cartilage in relation to obesity and severity of knee osteoarthritis. Cartilage 1947603518796122:458–472. https://doi.org/10.1177/1947603518796122CrossRef

42.

Gu HY, Yang M, Guo J, Zhang C, Lin LL, Liu Y, Wei RX (2019) Identification of the biomarkers and pathological process of osteoarthritis: weighted gene co-expression network analysis. Front Physiol 10:275. https://doi.org/10.3389/fphys.2019.00275CrossRefPubMedPubMedCentral

43.

Deguchi T, Hashizume H, Nakajima M, Teraguchi M, Akune T, Yamada H, Tanaka S, Yoshimura N, Nojima M, Yoshida M, Ikegawa S (2019) A population-based study identifies an association of THBS2 with intervertebral disc degeneration. Osteoarthr Cartil 27:1501–1507. https://doi.org/10.1016/j.joca.2019.06.001CrossRef

44.

Pritzker KP, Gay S, Jimenez SA, Ostergaard K, Pelletier JP, Revell PA, Salter D, van den Berg WB (2006) Osteoarthritis cartilage histopathology: grading and staging. Osteoarthr Cartil 14:13–29. https://doi.org/10.1016/j.joca.2005.07.014CrossRef

45.

Imagawa K, de Andrés MC, Hashimoto K, Pitt D, Itoi E, Goldring MB, Roach HI, Oreffo RO (2011) The epigenetic effect of glucosamine and a nuclear factor-kappa B (NF-kB) inhibitor on primary human chondrocytes--implications for osteoarthritis. Biochem Biophys Res Commun 405:362–367. https://doi.org/10.1016/j.bbrc.2011.01.007CrossRefPubMedPubMedCentral

46.

Asthana C, Peterson GM, Shastri MD, Jones G, Patel RP (2020) Variation in plasma levels of glucosamine with chronic dosing: a possible reason for inconsistent clinical outcomes in osteoarthritis. Clin Ther 42:e140–e149. https://doi.org/10.1016/j.clinthera.2020.06.009CrossRefPubMed

Titel: Identification of abnormally methylated–differentially expressed genes and pathways in osteoarthritis: a comprehensive bioinformatic study
verfasst von: Linli Zheng
Weishen Chen
Guoyan Xian
Baiqi Pan
Yongyu Ye
Minghui Gu
Yinyue Ma
Ziji Zhang
Puyi Sheng
Publikationsdatum: 09.01.2021
Verlag: Springer International Publishing
Erschienen in: Clinical Rheumatology / Ausgabe 8/2021
Print ISSN: 0770-3198
Elektronische ISSN: 1434-9949
DOI: https://doi.org/10.1007/s10067-020-05539-w

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Live-Webinar "Urologie und Sexualmedizin in der Praxis"

Springer Medizin

Identification of abnormally methylated–differentially expressed genes and pathways in osteoarthritis: a comprehensive bioinformatic study