title: Effects of bisphosphonate treatment on DNA methylation in osteonecrosis of the jaw.
abstract: 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 (p<1.31E-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.
authors.affiliation: Human Genetics Foundation (HuGeF), Turin, Italy. Electronic address: silvia.polidoro@hugef.org.
authors.forename: Silvia
authors.initials: S
authors.lastname: Polidoro
authors.forename: Roberto
authors.initials: R
authors.lastname: Broccoletti
authors.forename: Gianluca
authors.initials: G
authors.lastname: Campanella
authors.forename: Cornelia
authors.initials: C
authors.lastname: Di Gaetano
authors.forename: Elisa
authors.initials: E
authors.lastname: Menegatti
authors.forename: Matteo
authors.initials: M
authors.lastname: Scoletta
authors.forename: Ennio
authors.initials: E
authors.lastname: Lerda
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Matullo
authors.forename: Paolo
authors.initials: P
authors.lastname: Vineis
authors.forename: Daniela
authors.initials: D
authors.lastname: Berardi
authors.forename: Crispian
authors.initials: C
authors.lastname: Scully
authors.forename: Paolo G
authors.initials: PG
authors.lastname: Arduino
mesh_terms: D000328:Adult; D000368:Aged; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019175:DNA Methylation / Q000187:drug effects* / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism; D004164:Diphosphonates / Q000008:administration & dosage / Q000009:adverse effects*; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008334:Mandible / Q000378:metabolism* / Q000473:pathology; D008437:Maxilla / Q000378:metabolism* / Q000473:pathology; D008798:Mevalonic Acid / Q000378:metabolism; D008875:Middle Aged; D011393:Procollagen-Proline Dioxygenase / Q000235:genetics / Q000378:metabolism; D053669:Syndecan-2 / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D004164:Diphosphonates; C095472:ERCC8 protein, human; C508245:SDC2 protein, human; D014157:Transcription Factors; D053669:Syndecan-2; D011393:Procollagen-Proline Dioxygenase; C568061:P3H2 protein, human; D045643:DNA Repair Enzymes; D008798:Mevalonic Acid
keywords: 27K beadchip; 3-hydroxy-3-methylglutaryl-coenzyme A; Alendronate; BMP; BP; Bisphosphonate treatment; Bisphosphonate-related osteonecrosis of the jaws; CBPE; DM; ECM; HMG-CoA; Illumina Infinium HumanMethylation27 BeadChip; Infinium HumanMethylation27 BeadChip; N-BP; Zoledronate; bisphosphonates; bone morphogenetic protein; cumulative BP exposure; differentially methylated; extracellular matrix; nitrogen-containing bisphosphonates