Genome-Wide DNA Methylation Study Identifies Significant Epigenomic Changes in Osteoarthritic Subchondral Bone and Similarity to Overlying Cartilage

Overview

Journal Arthritis Rheumatol

Publisher Wiley

Specialty Rheumatology

Date 2015 Dec 30

PMID 26713865

Citations 41

Authors

Matlock A Jeffries

Madison Donica

Lyle W Baker

Michael E Stevenson

Anand C Annan

Mary Beth Humphrey

Judith A James

Amr H Sawalha

Affiliations

Soon will be listed here.

Abstract

Objective: To perform a genome-wide DNA methylation study to identify differential DNA methylation patterns in subchondral bone underlying eroded and intact cartilage from patients with hip osteoarthritis (OA) and to compare these with DNA methylation patterns in overlying cartilage.

Methods: Genome-wide DNA methylation profiling using Illumina HumanMethylation 450 arrays was performed on eroded and intact cartilage and subchondral bone from within the same joint of 12 patients undergoing hip arthroplasty. Genes with differentially methylated CpG sites were analyzed to identify shared pathways, upstream regulators, and overrepresented gene ontologies, and these patterns were compared with those of the overlying cartilage. Histopathology was graded by modified Mankin score and assessed for correlation with DNA methylation.

Results: We identified 7,316 differentially methylated CpG sites in subchondral bone underlying eroded cartilage, most of which (∼75%) were hypomethylated, and 1,397 sites in overlying eroded cartilage, 126 of which were shared. Samples clustered into 3 groups with distinct histopathologic scores. We observed differential DNA methylation of genes including the RNA interference-processing gene AGO2, the growth factor TGFB3, the OA suppressor NFATC1, and the epigenetic effector HDAC4. Among known susceptibility genes in OA, 32 were differentially methylated in subchondral bone, 8 were differentially methylated in cartilage, and 5 were shared. Upstream regulator analysis using differentially methylated genes in OA subchondral bone showed a strong transforming growth factor β1 signature (P = 1 × 10(-40) ) and a tumor necrosis factor family signature (P = 3.2 × 10(-28) ), among others.

Conclusion: Our data suggest the presence of an epigenetic phenotype associated with eroded OA subchondral bone that is similar to that of overlying eroded OA cartilage.

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References

Verbruggen G, Wittoek R, Vander Cruyssen B, Elewaut D . Tumour necrosis factor blockade for the treatment of erosive osteoarthritis of the interphalangeal finger joints: a double blind, randomised trial on structure modification. Ann Rheum Dis. 2011; 71(6):891-8. PMC: 3371224. DOI: 10.1136/ard.2011.149849. View

Kandeel M, Al-Taher A, Nakashima R, Sakaguchi T, Kandeel A, Nagaya Y . Bioenergetics and gene silencing approaches for unraveling nucleotide recognition by the human EIF2C2/Ago2 PAZ domain. PLoS One. 2014; 9(5):e94538. PMC: 4008379. DOI: 10.1371/journal.pone.0094538. View

Koga T, Matsui Y, Asagiri M, Kodama T, de Crombrugghe B, Nakashima K . NFAT and Osterix cooperatively regulate bone formation. Nat Med. 2005; 11(8):880-5. DOI: 10.1038/nm1270. View

Kou S, Wu Y . Meta-analysis of tumor necrosis factor alpha -308 polymorphism and knee osteoarthritis risk. BMC Musculoskelet Disord. 2014; 15:373. PMC: 4289255. DOI: 10.1186/1471-2474-15-373. View

Rollin R, Marco F, Jover J, Garcia-Asenjo J, Rodriguez L, Lopez-Duran L . Early lymphocyte activation in the synovial microenvironment in patients with osteoarthritis: comparison with rheumatoid arthritis patients and healthy controls. Rheumatol Int. 2008; 28(8):757-64. DOI: 10.1007/s00296-008-0518-7. View

Kammermann J, Kincaid S, Rumph P, Baird D, Visco D . Tumor necrosis factor-alpha (TNF-alpha) in canine osteoarthritis: Immunolocalization of TNF-alpha, stromelysin and TNF receptors in canine osteoarthritic cartilage. Osteoarthritis Cartilage. 1996; 4(1):23-34. DOI: 10.1016/s1063-4584(96)80004-5. View

Yu W, Gwinn M, Clyne M, Yesupriya A, Khoury M . A navigator for human genome epidemiology. Nat Genet. 2008; 40(2):124-5. DOI: 10.1038/ng0208-124. View

Kunisch E, Kinne R, Alsalameh R, Alsalameh S . Pro-inflammatory IL-1beta and/or TNF-alpha up-regulate matrix metalloproteases-1 and -3 mRNA in chondrocyte subpopulations potentially pathogenic in osteoarthritis: in situ hybridization studies on a single cell level. Int J Rheum Dis. 2014; 19(6):557-66. DOI: 10.1111/1756-185X.12431. View

Zhen G, Wen C, Jia X, Li Y, Crane J, Mears S . Inhibition of TGF-β signaling in mesenchymal stem cells of subchondral bone attenuates osteoarthritis. Nat Med. 2013; 19(6):704-12. PMC: 3676689. DOI: 10.1038/nm.3143. View

10.

Yin W, Park J, Loeser R . Oxidative stress inhibits insulin-like growth factor-I induction of chondrocyte proteoglycan synthesis through differential regulation of phosphatidylinositol 3-Kinase-Akt and MEK-ERK MAPK signaling pathways. J Biol Chem. 2009; 284(46):31972-81. PMC: 2797269. DOI: 10.1074/jbc.M109.056838. View

11.

Massip L, Ectors F, Deprez P, Maleki M, Behets C, Lengele B . Expression of Hoxa2 in cells entering chondrogenesis impairs overall cartilage development. Differentiation. 2007; 75(3):256-67. DOI: 10.1111/j.1432-0436.2006.00132.x. View

12.

Silvestri T, Pulsatelli L, Dolzani P, Facchini A, Meliconi R . Elevated serum levels of soluble interleukin-4 receptor in osteoarthritis. Osteoarthritis Cartilage. 2006; 14(7):717-9. DOI: 10.1016/j.joca.2006.02.015. View

13.

Valdes A, Oene M, Hart D, Surdulescu G, Loughlin J, Doherty M . Reproducible genetic associations between candidate genes and clinical knee osteoarthritis in men and women. Arthritis Rheum. 2006; 54(2):533-9. DOI: 10.1002/art.21621. View

14.

Prasadam I, Mao X, Shi W, Crawford R, Xiao Y . Combination of MEK-ERK inhibitor and hyaluronic acid has a synergistic effect on anti-hypertrophic and pro-chondrogenic activities in osteoarthritis treatment. J Mol Med (Berl). 2012; 91(3):369-80. DOI: 10.1007/s00109-012-0953-5. View

15.

Delgado-Calle J, Fernandez A, Sainz J, Zarrabeitia M, Sanudo C, Garcia-Renedo R . Genome-wide profiling of bone reveals differentially methylated regions in osteoporosis and osteoarthritis. Arthritis Rheum. 2012; 65(1):197-205. DOI: 10.1002/art.37753. View

16.

Yuan X, Meng H, Wang Y, Peng J, Guo Q, Wang A . Bone-cartilage interface crosstalk in osteoarthritis: potential pathways and future therapeutic strategies. Osteoarthritis Cartilage. 2014; 22(8):1077-89. DOI: 10.1016/j.joca.2014.05.023. View

17.

Chiang D, Cuthbertson D, Ruiz F, Li N, Pereira F . A coregulatory network of NR2F1 and microRNA-140. PLoS One. 2013; 8(12):e83358. PMC: 3857795. DOI: 10.1371/journal.pone.0083358. View

18.

Martel-Pelletier J, Di Battista J, Lajeunesse D, Pelletier J . IGF/IGFBP axis in cartilage and bone in osteoarthritis pathogenesis. Inflamm Res. 1998; 47(3):90-100. DOI: 10.1007/s000110050288. View

19.

Roemer F, Guermazi A, Javaid M, Lynch J, Niu J, Zhang Y . Change in MRI-detected subchondral bone marrow lesions is associated with cartilage loss: the MOST Study. A longitudinal multicentre study of knee osteoarthritis. Ann Rheum Dis. 2008; 68(9):1461-5. PMC: 2905622. DOI: 10.1136/ard.2008.096834. View

20.

Magnano M, Chakravarty E, Broudy C, Chung L, Kelman A, Hillygus J . A pilot study of tumor necrosis factor inhibition in erosive/inflammatory osteoarthritis of the hands. J Rheumatol. 2007; 34(6):1323-7. View