A Pilot Analysis of Genome-Wide DNA Methylation Patterns in Mouse Cartilage Reveals Overlapping Epigenetic Signatures of Aging and Osteoarthritis.

ACR Open Rheumatology Pub Date : 2022-12-01 Epub Date: 2022-10-17 DOI:10.1002/acr2.11506

Vladislav Izda, Christopher M Dunn, Emmaline Prinz, Leoni Schlupp, Emily Nguyen, Cassandra Sturdy, Matlock A Jeffries

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Abstract

Objective: Cartilage epigenetic changes are strongly associated with human osteoarthritis (OA). However, the influence of individual environmental OA risk factors on these epigenetic patterns has not been determined; herein we characterize cartilage DNA methylation patterns associated with aging and OA in a mouse model.

Methods: Murine knee cartilage DNA was extracted from healthy young (16-week, n = 6), old (82-week, n = 6), and young 4-week post-destabilization of the medial meniscus (DMM) OA (n = 6) C57BL6/J mice. Genome-wide DNA methylation patterns were determined via Illumina BeadChip. Gene set enrichment analysis was performed by Ingenuity Pathway Analysis. The top seven most differentially methylated positions (DMPs) were confirmed by pyrosequencing in an independent animal set. Results were compared to previously published human OA methylation data.

Results: Aging was associated with 20,940 DMPs, whereas OA was associated with 761 DMPs. Merging these two conditions revealed 279 shared DMPs. All demonstrated similar directionality and magnitude of change (Δβ 1.0% ± 0.2%, mean methylation change ± SEM). Shared DMPs were enriched in OA-associated pathways, including RhoA signaling (P = 1.57 × 10^-4 ), protein kinase A signaling (P = 3.38 × 10^-4 ), and NFAT signaling (P = 6.14 × 10^-4 ). Upstream regulators, including TET3 (P = 6.15 × 10^-4 ), immunoglobulin (P = 6.14 × 10^-4 ), and TLR7 (P = 7.53 × 10^-4 ), were also enriched. Pyrosequencing confirmed six of the seven top DMPs in an independent cohort.

Conclusion: Aging and early OA following DMM surgery induce similar DNA methylation changes within a murine OA model, suggesting that aging may induce pro-OA epigenetic "poising" within articular cartilage. Future research should focus on confirming and expanding these findings to other environmental OA risk factors, including obesity, as well as determining late OA changes in mice.

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小鼠软骨全基因组DNA甲基化模式的初步分析揭示了衰老和骨关节炎的重叠表观遗传特征。

目的：软骨表观遗传改变与人类骨关节炎（OA）密切相关。然而，个体环境OA危险因素对这些表观遗传模式的影响尚未确定；在此，我们在小鼠模型中表征了与衰老和OA相关的软骨DNA甲基化模式。方法：提取健康幼年（16周，n = 6）、老年（82周，n = 6）和幼年（6周，n = 6） C57BL6/J内侧半月板（DMM） OA失稳后4周的小鼠膝关节软骨DNA。通过Illumina BeadChip检测全基因组DNA甲基化模式。基因集富集分析采用Ingenuity Pathway analysis。在一组独立的动物中，通过焦磷酸测序证实了前7个差异甲基化位点（dmp）。结果与先前发表的人类OA甲基化数据进行了比较。结果：衰老与20,940例dmp相关，而OA与761例dmp相关。将这两种情况合并后，发现共有279个dmp。所有研究均显示出相似的方向性和变化幅度（Δβ 1.0%±0.2%，平均甲基化变化±SEM）。共享dmp富集于oa相关通路，包括RhoA信号通路（P = 1.57 × 10-4）、蛋白激酶A信号通路（P = 3.38 × 10-4）和NFAT信号通路（P = 6.14 × 10-4）。上游调节因子包括TET3 （P = 6.15 × 10-4）、免疫球蛋白（P = 6.14 × 10-4）和TLR7 （P = 7.53 × 10-4）也富集。焦磷酸测序在一个独立队列中证实了7个顶级dmp中的6个。结论：在小鼠骨性关节炎模型中，衰老和DMM手术后的早期骨性关节炎诱导了相似的DNA甲基化变化，表明衰老可能诱导关节软骨内的促骨性关节炎表观遗传“中毒”。未来的研究应侧重于证实并将这些发现扩展到其他环境OA危险因素，包括肥胖，以及确定小鼠晚期OA的变化。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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ACR Open Rheumatology

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