Aim
DNA methylation has a key role in gene regulation in many tissues, but little is known of its involvement in bone homeostasis. No information is available about bisphosphonates related osteonecrosis of the jaw (BRONJ) and altered methylation.
This study investigates the role of DNA methylation in the pathogenesis of BRONJ as a consequence of treatment with intravenous nitrogenous-containing bisphosphonates (zoledronic acid).
Methods
We performed an epigenome-wide association study using the Illumina Infinium Human Methylation 27 BeadChip assay in peripheral blood samples from 80 patients treated with nitrogenous BP, including 40 who developed BRONJ.
Results
Logistic regression analysis confirmed a positive association between cumulative exposure and risk of developing BRONJ. The analysis of the cumulative BP-exposure distribution indicated that cases were slightly more exposed to BP than controls, and that cases diagnosed with BRONJ in both mandible and maxilla were significantly more exposed to BP than controls. Logistic regression analysis confirmed the positive association between cumulative BP exposure and risk of BRONJ. 34 probes, corresponding to 33 differentially methylated (DM) genes, were significantly associated with cumulative BP exposure; ERCC8, LEPREL1, and SDC2 genes showed highly statistically significant differences in methylation levels by BP exposure.
Conclusion
Enrichment analysis, combining DM genes with genes involved in HMG-CoA reductase pathway, evidenced that BP treatment can affect the methylation pattern of genes involved in extracellular matrix organization, and inflammatory response, leading to more frequent adverse effects such as BRONJ. Differences in DNA methylation induced by BP treatment could be involved in the pathogenesis of bone lesions. Disturbing the healing at any stage, particularly the formation of the provisional matrix, could compromise the entire process and lead to a more frequent occurrence of side effects such as BRONJ.
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