Distinct DNA methylation profiles in bone and blood of osteoporotic and healthy postmenopausal women

Abstract

DNA methylation affects expression of associated genes and may contribute to the missing genetic effects from genome-wide association studies of osteoporosis. To improve insight into the mechanisms of postmenopausal osteoporosis, we combined transcript profiling with DNA methylation analyses in bone. RNA and DNA were isolated from 84 bone biopsies of postmenopausal donors varying markedly in bone mineral density (BMD). In all, 2529 CpGs in the top 100 genes most significantly associated with BMD were analyzed. The methylation levels at 63 CpGs differed significantly between healthy and osteoporotic women at 10% false discovery rate (FDR). Five of these CpGs at 5% FDR could explain 14% of BMD variation. To test whether blood DNA methylation reflect the situation in bone (as shown for other tissues), an independent cohort was selected and BMD association was demonstrated in blood for 13 of the 63 CpGs. Four transcripts representing inhibitors of bone metabolism-MEPE, SOST, WIF1, and DKK1-showed correlation to a high number of methylated CpGs, at 5% FDR. Our results link DNA methylation to the genetic influence modifying the skeleton, and the data suggest a complex interaction between CpG methylation and gene regulation. This is the first study in the hitherto largest number of postmenopausal women to demonstrate a strong association among bone CpG methylation, transcript levels, and BMD/fracture. This new insight may have implications for evaluation of osteoporosis stage and susceptibility.

Ex Vivo Organ Cultures as Models to Study Bone Biology

“…Similar to our in vitro studies, the expression of Sost in ex vivo bone organ cultures was increased . Clinical studies inspired by these initial findings demonstrated that Sost/sclerostin expression negatively correlates with DNA methylation at the Sost proximal promoter in several patient populations . In a different set of experiments, we employed ex vivo human bone organ cultures to determine the translatability of findings found in mouse models.…”

“…(62) Clinical studies inspired by these initial findings demonstrated that Sost/sclerostin expression negatively correlates with DNA methylation at the Sost proximal promoter in several patient populations. (63,64) In a different set of experiments, we employed ex vivo human bone organ cultures to determine the translatability of findings found in mouse models. As described previously, PTH increases the expression of Mmp14 in murine bone, which in turn stimulates the production of sRankl.…”

Identification of an Epigenetic Signature of Osteoporosis in Blood DNA of Postmenopausal Women

“…Another study criterion was the use of femoral neck and lumbar spine BMD, and different analytical methods and cut‐off points were used as compared to our study. In another study, change in methylation status in blood of osteoporotic men and women was compared with bone biopsies of osteoporotic subjects . Among 63 CpG identified in bone biopsies, 13 showed correlations with BMD in blood.…”

“…Peripheral blood monocytes, which are precursors of bone‐resorbing osteoclasts, secrete several osteoclastogenic cytokines that are implicated in the pathogenesis of OP . Recently, DNA methylation analysis of bone biopsies of postmenopausal women with variable BMD showed differential methylation of CpGs, some of which could be reproduced in blood DNA …”

The role of DNA methylation in the disorders of bone metabolism

“…Поэтому все чаще возникают проекты, направленные на исследование паттернов ДНКметилирования непо средственно в костном биопсийном материале. Попытка охарактеризовать паттерны метилирования генов, которые значительно ассоциированы с вариабельностью уровня МПКТ у 84 постменопаузальных женщин, была предпри нята в работе (Reppe et al, 2017). Проанализировано более 480 тыс.…”