Cindy Boer

Epigenomics in bone and cartilage disease | 37 1.2 DNMTs and subsequently DNAmethylation. The methylation of promoters regulates the transcriptional activity not only of protein‐coding genes but also of miRNAs and other non‐coding RNAs. In turn, miRNAs contribute to modulating the synthesis of DNMTs and histone‐modifying enzymes. lncRNAs also influence the activity of genes encoding chromatin‐modifying enzymes and miRNAs[10]. Although the sequence of molecular steps is still unclear, there is evidence for the notion that DNA, RNA, and histone pro- teins, along with their modifications, act in a concerted fashion to bring about chroma- tin states that are important for dictating genomic functions[8] ( Figure 1 ). Epigenetic programming during development From the moment of conception to adulthood, the environment shapes the phenotypic output. It is thought that there are certain “high sensitive” windows especially during development that have major influence on the epigenome[11]. The developmental or- igins of health and disease concept suggests that poor developmental experience can increase the risk of non‐communicable diseases in later life, including cardiovascular, metabolic, neurological, and skeletal disorders[12]. A variety of mechanisms, including DNA methylation and other long‐lasting epigenetic marks, may mediate the influence of the environment on the developing organism[13, 14]. A few studies have explored the role of developmental factors in skeletal disorders. In a systematic review of the literature, a positive association between birth weight and bone mass was clear among children, unclear among adolescents, and weak among adults. The effect was stronger on bone mineral content (BMC) than on BMD regardless of age[15]. This suggests that intrauterine growth is more closely related to bone size than to bone density and that the effect tends to be mitigated by postnatal influences. It seems that early life expo- sures are important for determining peak bone mass, which may be a reflection of the combined influence of intrauterine and early postnatal environmental exposures. Maternal nutrition and specifically thematernal vitamin D status may be a critical factor for an adequate intrauterine growth rate[16], but studies have shown conflicting results.[17]. Rather surprisingly, in the Rotterdam cohort, severe maternal 25(OH)D de- ficiency (<25nmol/L) during mid‐pregnancy was associated with higher offspring BMC and bone area at 6 years of age, while no associations were found between maternal vitamin D status and offspring BMD[18]. In experimental animals, vitamin D status has a transgenerational effect on the methylation of multiple genes[19]. However, human studies about the relationship between maternal vitamin D levels and DNA methylation in offspring have given controversial results[16]. Therefore, the actual relevance of ma- ternal vitamin D on DNA methylation and the bone mass of the offspring is still unclear.