Effects of bisphosphonate treatment on DNA methylation in osteonecrosis of the jaw
| Autor: | Giuseppe Matullo, Matteo Scoletta, Elisa Menegatti, Gianluca Campanella, Cornelia Di Gaetano, Crispian Scully, Silvia Polidoro, Paolo G. Arduino, Ennio Lerda, Daniela Berardi, Paolo Vineis, Roberto Broccoletti |
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| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Adult
Male medicine.medical_specialty Health Toxicology and Mutagenesis Bisphosphonate-related osteonecrosis of the jaws Osteoporosis Bisphosphonate treatment Procollagen-Proline Dioxygenase Cumulative Exposure Mevalonic Acid Mandible In Vitro Techniques Gastroenterology Internal medicine Genetics medicine Maxilla Humans Hypocalcaemia Illumina Infinium HumanMethylation27 BeadChip Adverse effect Aged Diphosphonates Alendronate business.industry Cancer DNA Methylation Middle Aged medicine.disease Extracellular Matrix ERCC8 DNA Repair Enzymes Zoledronate DNA methylation Bisphosphonate-Associated Osteonecrosis of the Jaw Female Syndecan-2 Osteonecrosis of the jaw business Transcription Factors |
| Popis: | Bisphosphonates are used in the treatment of hypocalcaemia, mainly in cancer and osteoporosis. Some patients experience adverse events, such as BP-related osteonecrosis of the jaw (BRONJ). DNA methylation plays a key role in gene regulation in many tissues, but its involvement in bone homeostasis is not well characterized, and no information is available regarding altered methylation in BRONJ. Using the Illumina Infinium HumanMethylation27 BeadChip assay, we performed an epigenome-wide association study in peripheral blood samples from 68 patients treated with nitrogenous BP, including 35 with BRONJ. Analysis of the estimated cumulative BP exposure distribution indicated that the exposure of the case group to BP was slightly higher than that of the control group; more severely affected cases (i.e., with BRONJ in both mandible and maxilla) were significantly more exposed to BP than were those with BRONJ only in the mandible or maxilla (one-sided Wilcoxon rank sum test, p=0.002). Logistic regression analysis confirmed the positive association between cumulative bisphosphonates exposure and risk of BRONJ (OR 1.015 per mg of cumulative exposure, 95% CI 1.004-1.032, p=0.036). Although no statistically significant differences were observed between case and control groups, methylation levels of probes mapping on three genes, ERCC8, LEPREL1 and SDC2, were strongly associated with cumulative BP exposure levels (p1.31E-007). Enrichment analysis, combining differentially methylated genes with genes involved in the mevalonate pathway, showed that BP treatment can affect the methylation pattern of genes involved in extracellular matrix organization and inflammatory responses, leading to more frequent adverse effects such as BRONJ. Differences in DNA methylation induced by BP treatment could be involved in the pathogenesis of the bone lesion. |
| Databáze: | OpenAIRE |
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