Session Information
Date: Monday, November 9, 2015
Title: Biology and Pathology of Bone and Joint Poster I: Osteoarthritis Pathogenesis
Session Type: ACR Poster Session B
Session Time: 9:00AM-11:00AM
Background/Purpose: Osteoarthritis (OA) is a leading cause of chronic disability affecting a majority of individuals over age 70. Outside of cartilage, little is known regarding changes in DNA methylation that occur regionally within OA joints. Herein, we performed global DNA methylation analysis of subchondral bone underlying eroded and intact regions of the OA hip joints and compared it to our previous analysis of OA cartilage.
Methods: Twelve femoral heads were obtained from hip arthroplasty for primary OA. From eroded and intact areas of each joint, articular cartilage and 1cm-deep cores of underlying subchondral bone were dissected, frozen in liquid nitrogen, and DNA extracted. Methylation profiling of >485,000 sites was performed using Illumina HumanMethylation450 arrays; differential methylation was defined as FDR-corrected p<0.01 with absolute methylation difference of at least 15%. Pyrosequencing confirmed the four most differentially methylated sites.
Results: We identified 5477 hypo- and 1839 hypermethylated CpG sites in subchondral bone underlying eroded cartilage compared to intact tissue, corresponding to 2290 and 621 genes, respectively. The most hypomethylated genes included the RISC component EIF2C2, ERGIc1, the cell adhesion molecule LPP, and the MAPK deactivator DUSP1, whereas the most hypermethylated genes were HOXA7, CD4, CD6, and CD28. Pathway analysis revealed genes involved in cancer (n=96, p=1.38E-12), axonal guidance (n=104, p=4×10-11), NFAT signaling (n=55, p=4×10-10), and ERK/MAPK signaling (n=55, p=1×10-9). The most highly associated upstream regulators included TGFβ1 (p=3×10-39), TNF (p=1×10-27), and p53 (p=8×10-24). Comparing subchondral bone results to our OA cartilage data, 153 methylation sites from 420 genes were differentially methylated in both OA cartilage and subchondral bone. Significant overlap in upstream regulators and many shared pathways were found including ERK/MAPK-, NFAT-, IGF-1-, and PTEN-signaling. Among upstream regulators, TGFβ, miR-124, angiotensinogen, RANKL, and p38 MAPK were all highly associated with differentially methylated genes in both cartilage and subchondral bone. Four previously-identified OA susceptibility genes, COL11A2, FTO, LRP5, and NCOR2, were differentially methylated in both subchondral bone and overlying cartilage.
Conclusion: Our data implicate epigenetic dysregulation of several genes and pathways in localized areas of subchondral bone underlying OA damage. Although relatively few differentially methylated sites were shared among cartilage and subchondral bone, there was substantial overlap among pathways and upstream regulators. Our work strengthens the notion that a dysregulated epigenome among subchondral bone and cartilage are intimately linked in the pathogenesis of OA, and reiterates that OA represents a disease of the entire joint organ.
To cite this abstract in AMA style:
Jeffries MA, Andrews M, Humphrey MB, James JA, Sawalha AH. Global DNA Methylation Analysis of Osteoarthritic Subchondral Bone Reveals Significant Regional Variation and Similarity to Overlying Cartilage [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/global-dna-methylation-analysis-of-osteoarthritic-subchondral-bone-reveals-significant-regional-variation-and-similarity-to-overlying-cartilage/. Accessed .« Back to 2015 ACR/ARHP Annual Meeting
ACR Meeting Abstracts - https://acrabstracts.org/abstract/global-dna-methylation-analysis-of-osteoarthritic-subchondral-bone-reveals-significant-regional-variation-and-similarity-to-overlying-cartilage/