Prospective studies examining early maternal exposure to trace metal (TM) mixtures and their effects on offspring remain limited. We analyzed data regarding maternal plasma trace metal concentrations and bone mineral density (BMD) for 220 children aged 3-6 years from the Guangxi Zhuang Birth Cohort. Inductively coupled plasma-mass spectrometry was used to measure 22 trace metal concentrations-Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, As, Se, Rb, Sr, Mo, Cd, Sb, Cs, Ba, W, Tl, Pb, and U-in maternal plasma samples collected before 13 weeks of gestation. BMD Z-scores in children were assessed using quantitative ultrasound. Generalized linear models, restricted cubic spline (RCS) models, principal component analysis, Bayesian kernel machine regression, and quantile-based g-computation (qgcomp) were used to evaluate the associations between maternal plasma metal levels and BMD Z-scores in the child. Higher maternal Fe concentration was correlated with lower child BMD Z-scores (β [95% confidence interval]: - 1.374 [- 2.426 to - 0.323], p = 0.011). Increased Pb exposure was correlated with higher Z-scores (β [95% CI]: 1.035 [0.150-1.920], p = 0.023), corroborated by the RCS model (p = 0.031). Ti levels exceeding the median were associated with increased BMD Z-scores (p = 0.027). Increased BMD in children was associated with higher levels of metal mixtures, including Mn, V, Ti, U, Ni, Zn, Sr, Pb, W, and Co. Pb appears to play a primary role in this effect. TM exposure during early pregnancy is associated with BMD in children; however, additional longitudinal and experimental studies are required to confirm this conclusion.

From fertilisation to delivery, calcium must be transported into and within the foetoplacental unit for intracellular signalling. This requires very rapid, precisely located Ca2+ transfers. In addition, from around the eighth week of gestation, increasing amounts of calcium must be routed directly from maternal blood to the foetus for bone mineralisation through a flow-through system, which does not impact the intracellular Ca2+ concentration. These different processes are mediated by numerous membrane-sited Ca2+ channels, transporters, and exchangers. Understanding the mechanisms is essential to direct interventions to optimise foetal development and postnatal bone health and to protect the mother and foetus from pre-eclampsia. Ethical issues limit the availability of human foetal tissue for study. Our insight into the processes of placental Ca2+ handling is advancing rapidly, enabled by developing genetic, analytical, and computer technology. Because of their diverse sources, the reports of new findings are scattered. This review aims to pull the data together and to highlight areas of uncertainty. Areas needing clarification include trafficking, membrane expression, and recycling of channels and transporters in the placental microvilli; placental metabolism of vitamin D in gestational diabetes and pre-eclampsia; and the vascular effects of increased endothelial Orai expression by pregnancy-specific beta-1-glycoproteins PSG1 and PSG9.

ANRIL (Antisense Noncoding RNA in the INK4 Locus), a long non-coding RNA encoded in the human chromosome 9p21 region, is a critical factor for regulating gene expression by interacting with multiple proteins and miRNAs. It has been found to play important roles in various cellular processes, including cell cycle control and proliferation. Dysregulation of ANRIL has been associated with several diseases like cancers and cardiovascular diseases, for instance. Understanding the oncogenic role of ANRIL and its potential as a diagnostic and prognostic biomarker in cancer is crucial. This review provides insights into the regulatory mechanisms and oncogenic significance of the 9p21 locus and ANRIL in cancer.

Long non-coding RNAs (lncRNA) have been identified as essential components having considerable modulatory impactson biological activities through altering gene transcription, epigenetic changes, and protein translation. Cyclin-dependent kinase inhibitor 2B antisense RNA 1 (CDKN2B-AS1), a recently discovered lncRNA, was shown to be substantially elevated in various cancers.Furthermore, via modulation ofvarious signalingaxes, it is effectively connected to the control of critical cancer-associatedbiological pathways likecell proliferation, apoptosis, cell cycle, epithelial-mesenchymal transition(EMT), invasion, and migration. Considering the crucial functions ofCDKN2B-AS1in cancer onset and development, this lncRNA offers immense therapeutic implications for usage as a new diagnostic or treatment approach. In this article, we evaluate the most recent discoveries made into the functions of the lncRNA CDKN2B-AS1 in cancer, in addition to its prospect asbeneficial properties,prognostic anddiagnostic biomarkersin the cancer-related treatment, emphasizingits participation in a broad network of signalingaxes whichcould affectvariouscancers and investigating its promising therapeutic possibility.

Environmental toxicants can regulate gene expression in the absence of DNA mutations via epigenetic mechanisms such as DNA methylation, histone modifications, and non-coding RNAs' (ncRNAs). Here, all three epigenetic modifications for seven important categories of diseases and the impact of eleven main environmental factors on epigenetic modifications were discussed. Epigenetic-related mechanisms are among the factors that could explain the root cause of a wide range of common diseases. Its overall impression on the development of diseases can help us diagnose and treat diseases, and besides, predict transgenerational and intergenerational effects. This comprehensive article attempted to address the relationship between environmental factors and epigenetic modifications that cause diseases in different categories. The studies main gap is that the precise role of environmentally-induced epigenetic alterations in the etiology of the disorders is unknown; thus, still more well-designed researches need to be accomplished to fill this gap. The present review aimed to first summarize the adverse effect of certain chemicals on the epigenome that may involve in the onset of particular disease based on in vitro and in vivo models. Subsequently, the possible adverse epigenetic changes that can lead to many human diseases were discussed.

Osteoporosis is a highly prevalent disease with distinct sex pattern. We aimed to estimate the sex specific incidence, prevalence, and disability-adjusted life (DALYs) years of osteoporosis between 1990 and 2019, with additional predictions from 2020 to 2034.

We collected osteoporosis disease burden data from the Global Burden of Disease study covering the years 1990 through 2019 in 204 countries and territories. The data included information on the number of incident cases of osteoporosis, DALYs, age-standardized incidence rates (ASIR), age-standardized prevalence rates (ASPR) and age-standardized DALYs rates. Additionally, we performed an age-period-cohort analysis to forecast the burden of osteoporosis.

The global number of incidence cases of osteoporosis, in 2019, reached 41.5 million cases. From 1990 to 2019, the low-middle socio-demographic index (SDI) region had the highest estimated annual percentage change in the world. Compared to males, female's ASIR and ASPR were all about 1.5 times higher than males for the same years in the same SDI regions. The projected global total number of incidence cases for osteoporosis between 2030 and 2034 is estimated to reach 263.2 million (154.4 million for females and 108.8 for males). Additionally, the burden in terms of DALYs is predicted to be 128.7 million (with 78.4 million for females and 50.3 million for males).

The global burden of osteoporosis is still increasing, mainly observed in high SDI countries. Females bear a burden 1.5 times higher than males in terms of incidence and DALYs. Steps should be taken to reduce the osteoporosis burden, especially in high SDI countries.

Osteoporosis, characterised by low bone mass, poor bone structure, and an increased risk of fracture, is a major public health problem. There is increasing evidence that the influence of the environment on gene expression, through epigenetic processes, contributes to variation in BMD and fracture risk across the lifecourse. Such epigenetic processes include DNA methylation, histone and chromatin modifications and non-coding RNAs. Examples of associations with phenotype include DNA methylation in utero linked to maternal vitamin D status, and to methylation of target genes such as OPG and RANKL being associated with osteoporosis in later life. Epigenome-wide association studies and multi-omics technologies have further revealed susceptibility loci, and histone acetyltransferases, deacetylases and methylases are being considered as therapeutic targets. This review encompasses recent advances in our understanding of epigenetic mechanisms in the regulation of bone mass and osteoporosis development, and outlines possible diagnostic and prognostic biomarker applications.

There is a huge number of noncoding RNA (ncRNA) transcripts in the cell with important roles in modulation of different mechanisms. ANRIL is a long ncRNA with 3.8 kb length that is transcribed in the opposite direction of the INK4/ARF locus in chromosome 9p21. It was shown that polymorphisms within this locus are associated with vascular disorders, notably coronary artery disease (CAD), which is considered as a risk factor for life-threatening events like myocardial infarction and stroke. ANRIL is subjected to a variety of splicing patterns producing multiple isoforms. Linear isoforms could be further transformed into circular ones by back-splicing. ANRIL regulates genes in atherogenic network in a positive or negative manner. This regulation is implemented both locally and remotely. While CAD is known as a proliferative disorder and cell proliferation plays a crucial role in the progression of atherosclerosis, the functions of ANRIL and CAD development are intertwined remarkably. This makes ANRIL a suitable target for diagnostic, prognostic, and even therapeutic aims. In this review, we tried to present a comprehensive appraisal on different aspects of ANRIL including its location, structure, isoforms, expression, and functions. In each step, the contribution of ANRIL to atherosclerosis is discussed.

Bone is a complex tissue that undergoes constant remodeling to maintain homeostasis, which requires coordinated multilineage differentiation and proper proliferation of mesenchymal stromal cells (MSCs). Mounting evidence indicates that a disturbance of bone homeostasis can trigger degenerative bone diseases, including osteoporosis and osteoarthritis. In addition to conventional genetic modifications, epigenetic modifications (i.e., DNA methylation, histone modifications, and the expression of noncoding RNAs) are considered to be contributing factors that affect bone homeostasis. Long noncoding RNAs (lncRNAs) were previously regarded as 'transcriptional noise' with no biological functions. However, substantial evidence suggests that lncRNAs have roles in the epigenetic regulation of biological processes in MSCs and related diseases. In this review, we summarized the interactions between lncRNAs and epigenetic modifiers associated with osteo-/adipogenic differentiation of MSCs and the pathogenesis of degenerative bone diseases and highlighted promising lncRNA-based diagnostic and therapeutic targets for bone diseases.

Nutritional rickets is an important disease in global health. Although nutritional rickets commonly manifests as bony deformities, there is an increased risk of life-threatening seizures secondary to hypocalcaemia. Dietary vitamin D deficiency is associated with the development of nutritional rickets among children and infants. This is especially true in populations of darker skinned individuals in high-latitude environments due to decreased ultraviolet light exposure, and in populations in tropical and subtropical climates due to cultural practices. A growing body of evidence has demonstrated that genetic factors might influence the likelihood of developing nutritional rickets by influencing an individual's susceptibility to develop deficiencies in vitamin D and/or calcium. This evidence has been drawn from a variety of different techniques ranging from traditional twin studies to next generation sequencing techniques. Additionally, the role of the epigenome in the development of rickets, although poorly understood, may be related to the effects of DNA methylation and non-coding RNAs on genes involved in bone metabolism. This review aims to provide an overview of the current evidence that investigates the genetic and epigenetic determinants of nutritional rickets.

Data evaluating changes in bone mineral density (BMD) in Down syndrome (DS) individuals remains controversial. Therefore, we conducted a systematic review and meta-analysis to better understand associations between BMD and DS. A systematic literature search of PubMed, EMBASE, Web of Science, and the Cochrane Library up until 1st January 2021 was conducted. We used the keywords "bone mineral density" and "Down Syndrome." Fifteen studies were included. Overall, our results showed a significant decrease in BMD of total body (TB BMD) [MD =  - 0.18; 95% CI (- 0.23 and - 0.12), P < 0.00001, I2 = 89%], total hip (TH BMD) [MD =  - 0.12; 95% CI (- 0.15 and - 0.10), P < 0.00001, I2 = 0%], lumbar spine (LS BMD) [MD =  - 0.12; 95% CI (- 0.14 and - 0.09), P < 0.00001, I2 = 18%], and femoral neck (FN BMD) [MD =  - 0.08; 95% CI (- 0.10 and - 0.06), P < 0.00001, I2 = 0%] in DS individuals when compared with controls. Moreover, the volumetric BMD of lumbar spine (LS vBMD) [MD =  - 0.01; 95% CI (- 0.02 and - 0.01), P = 0.0004, I2 = 19%] also showed a decreasing tendency while the volumetric BMD of the femoral neck (FN vBMD) [MD = 0.01; 95% CI (0.00 and 0.02), P = 0.02, I2 = 0%] was elevated in DS individuals versus controls. These findings demonstrated that individuals with DS had a decreased total and regional (TH, LS, and FN) BMD when compared with the general population. Additionally, when BMD was adjusted for skeletal volume, LS vBMD was also lower, while FN vBMD was elevated in DS individuals versus controls.

Optimisation of skeletal mineralisation in childhood is important to reduce childhood fracture and the long-term risk of osteoporosis and fracture in later life. One approach to achieving this is antenatal vitamin D supplementation. The Maternal Vitamin D Osteoporosis Study is a randomised placebo-controlled trial, the aim of which was to assess the effect of antenatal vitamin D supplementation (1000 IU/day cholecalciferol) on offspring bone mass at birth. The study has since extended the follow up into childhood and diversified to assess demographic, lifestyle and genetic factors that determine the biochemical response to antenatal vitamin D supplementation, and to understand the mechanisms underpinning the effects of vitamin D supplementation on offspring bone development, including epigenetics. The demonstration of positive effects of maternal pregnancy vitamin D supplementation on offspring bone development and the delineation of underlying biological mechanisms inform clinical care and future public-health policies.

Osteoporosis is a complex multifactorial condition of the musculoskeletal system. Osteoporosis and osteoporotic vertebral fracture (OVF) are associated with high medical costs and can lead to poor quality of life. Genetic factors are important in determining bone mass and structure, as well as any predisposition for bone degradation and OVF. However, genetic factors are not enough to explain osteoporosis development and OVF occurrence. Epigenetics describes a mechanism for controlling gene expression and cellular processes without altering DNA sequences. The main mechanisms in epigenetics are DNA methylation, histone modifications, and non-coding RNAs (ncRNAs). Recently, alterations in epigenetic mechanisms and their activity have been associated with osteoporosis and OVF. Here, we review emerging evidence that epigenetics contributes to the machinery that can alter DNA structure, gene expression, and cellular differentiation during physiological and pathological bone remodeling. A progressive understanding of normal bone metabolism and the role of epigenetic mechanisms in multifactorial osteopathy can help us better understand the etiology of the disease and convert this information into clinical practice. A deep understanding of these mechanisms will help in properly coordinating future individual treatments of osteoporosis and OVF.

Both environmental and genetic factors contribute to type 2 diabetes (T2D) risk. Dozens of T2D susceptibility loci have been identified by genome-wide association study. However, these loci account for only a small fraction of the familial T2D risk. We hypothesized that the gene-obesity interaction may contribute to the missing heritability.

Forty-eight T2D-associated variants were genotyped using the TaqMan OpenArray Genotyping System and iPLEX Sequenom MassARRAY platform in two separate studies. Obesity was defined according to multiple indexes (body mass index (BMI), waist circumference and waist-hip ratio). Multiplicative interactions were tested using general logistic regression to assess the gene-obesity interaction effect on T2D risk among a total of 6206 Chinese Hans.

After adjusting for the main effects of genes and obesity, as well as covariates (age, sex, smoking and alcohol consumption status), robust multiplicative interaction effects were observed between rs10811661 in CDKN2A/CDKN2B and multiple obesity indices (p ranged from 0.001 to 0.043 for BMI, waist circumference and waist-hip ratio). Obese individuals with the TT genotype had a drastically higher risk of T2D than normal weight individuals without the risk allele (OR=17.58, p<0.001). There were no significant differences between subgroups in the stratification analysis. Plausible biological explanations were established using a public database. However, there were no significant interaction effects between the other 47 single nucleotide polymorphism (SNPs) and obesity.

Our findings indicated that the CDKN2A/CDKN2B gene-obesity interaction significantly increases T2D risk in Chinese Hans. The interaction effect identified in our study may help to explain some of the missing heritability in the context of T2D susceptibility. In addition, the interaction effect may play a role in the precise prevention of T2D in Chinese individuals.

Bone diseases such as osteoarthritis, osteoporosis, and bone tumor present a severe public health problem. Osteogenic differentiation is a complex process associated with the differentiation of different cells, which could regulate transcription factors, cytokines, many signaling pathways, noncoding RNAs (ncRNAs), and epigenetic modulation. DNA methylation is a kind of stable epigenetic alterations in CpG islands without DNA sequence changes and is involved in cancer and other diseases, including bone development and homeostasis. ncRNAs can perform their crucial biological functions at the RNA level, and many findings have demonstrated essential functions of ncRNAs in osteogenic differentiation. In this review, we highlight current researches in DNA methylation of two relevant ncRNAs, including microRNAs and long noncoding RNAs, in the initiation and progression of osteogenesis and bone diseases.

To explore the association between methylation of antisense non-coding RNA in the INK4 locus (ANRIL) and coronary artery disease (CAD) development. Methylation levels of ANRIL in 100 subjects with CAD and 100 controls were quantitatively analyzed using Sequenom MassARRAY. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was used to identify novel pathways. Our analyses indicated that 7 to 8 CpG sites within the 2^nd CpG island located upstream of ANRIL, also known as cyclin-dependent kinase inhibitor 2B - antisense 1 (CDKN2B-AS1), are hyper-methylated in CAD subjects compared to controls (p = 0.034). The 40^th CpG site within the 2^nd CpG island located upstream of CDKN2B-AS1 was methylated to a lesser extent in CAD subjects compared to controls (p = 0.045). Both Pearson and Spearman analyses indicated that methylation levels were significantly associated with total cholesterol (r = 0.204, p = 0.004), fasting high-density lipoprotein cholesterol (r = 0.165, p = 0.020), and fasting low-density lipoprotein cholesterol (r = 0.265, p = 0.000). KEGG pathway analysis revealed a significant enrichment of genes associated with the tumor necrosis factor (TNF) signaling pathway. Among them, CCAAT/enhancer binding protein (C/EBPβ) was identified as a key transcription factor that promotes expression of CDKN2B-AS1 through promotor interaction. DNA methylation of the ANRIL promoter was significantly associated with CAD development in our study. Our analyses suggest that C/EBPβ is a key transcription factor that promotes CDKN2B-AS1 expression by directly interacting with the gene promotor mediated by TNF signaling.

Phenotypic variation in skeletal traits and diseases is the product of genetic and environmental factors. Epigenetic mechanisms include information-containing factors, other than DNA sequence, that cause stable changes in gene expression and are maintained during cell divisions. They represent a link between environmental influences, genome features, and the resulting phenotype. The main epigenetic factors are DNA methylation, posttranslational changes of histones, and higher-order chromatin structure. Sometimes non-coding RNAs, such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), are also included in the broad term of epigenetic factors. There is rapidly expanding experimental evidence for a role of epigenetic factors in the differentiation of bone cells and the pathogenesis of skeletal disorders, such as osteoporosis and osteoarthritis. However, different from genetic factors, epigenetic signatures are cell- and tissue-specific and can change with time. Thus, elucidating their role has particular difficulties, especially in human studies. Nevertheless, epigenomewide association studies are beginning to disclose some disease-specific patterns that help to understand skeletal cell biology and may lead to development of new epigenetic-based biomarkers, as well as new drug targets useful for treating diffuse and localized disorders. Here we provide an overview and update of recent advances on the role of epigenomics in bone and cartilage diseases. © 2019 American Society for Bone and Mineral Research.

We have previously demonstrated inverse associations between maternal 25(OH)-vitamin D status and perinatal DNA methylation at the retinoid-X-receptor-alpha (RXRA) locus and between RXRA methylation and offspring bone mass. In this study, we used an existing randomized trial to test the hypothesis that maternal gestational vitamin D supplementation would lead to reduced perinatal RXRA locus DNA methylation. The Maternal Vitamin D Osteoporosis Study (MAVIDOS) was a multicenter, double-blind, randomized, placebo-controlled trial of 1000 IU/day cholecalciferol or matched placebo from 14 weeks' gestation until delivery. Umbilical cord (fetal) tissue was collected at birth and frozen at -80°C (n = 453). Pyrosequencing was used to undertake DNA methylation analysis at 10 CpG sites within the RXRA locus (identified previously). T tests were used to assess differences between treatment groups in methylation at the three most representative CpG sites. Overall, methylation levels were significantly lower in the umbilical cord from offspring of cholecalciferol-supplemented mothers, reaching statistical significance at four CpG sites, represented by CpG5: mean difference in % methylation between the supplemented and placebo groups was -1.98% (95% CI, -3.65 to -0.32, p = 0.02). ENCODE (Encyclopedia of DNA Elements) evidence supports the functionality of this locus with strong DNase hypersensitivity and enhancer chromatin within biologically relevant cell types including osteoblasts. Enrichment of the enhancer-related H3K4me1 histone mark is also seen in this region, as are binding sites for a range of transcription factors with roles in cell proliferation, response to stress, and growth factors. Our findings are consistent with previous observational results and provide new evidence that maternal gestational supplementation with cholecalciferol leads to altered perinatal epigenetic marking, informing mechanistic understanding of early life mechanisms related to maternal vitamin D status, epigenetic marks, and bone development. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.

Osteoporosis is a "skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk of fracture" which, in light of demographic change, is becoming an increasing burden on health care worldwide. Increasing age and female gender are associated with the condition, although a wider range of clinical risk factors are being used increasingly to identify those at risk of osteoporosis and its most important sequelae, fracture.While osteoporosis and fracture have long been associated with women in the post-menopausal age, fracture incidence increases because of the ageing of our population. Interventions to abate the progression of osteoporosis and to prevent fractures must focus on the old and the very old. Evidence associating nutritional factors, particularly calcium and vitamin D are reviewed as are the association of falls risk with fracture and the potential for interventions to prevent falls. Finally, the assessment of frailty in the oldest old, associated sarcopenia and multi-morbidity are considered in the evaluation of fall and fracture risk and the management of osteoporosis in the ninth decade of life and beyond.

Osteoblastic differentiation is a multistep process characterized by osteogenic induction of mesenchymal stem cells, which then differentiate into proliferative pre-osteoblasts that produce copious amounts of extracellular matrix, followed by stiffening of the extracellular matrix, and matrix mineralization by hydroxylapatite deposition. Although these processes have been well characterized biologically, a detailed transcriptional analysis of murine primary calvaria osteoblast differentiation based on RNA sequencing (RNA-seq) analyses has not previously been reported. Here, we used RNA-seq to obtain expression values of 29,148 genes at four time points as murine primary calvaria osteoblasts differentiate in vitro until onset of mineralization was clearly detectable by microscopic inspection. Expression of marker genes confirmed osteogenic differentiation. We explored differential expression of 1386 protein-coding genes using unsupervised clustering and GO analyses. 100 differentially expressed lncRNAs were investigated by co-expression with protein-coding genes that are localized within the same topologically associated domain. Additionally, we monitored expression of 237 genes that are silent or active at distinct time points and compared differential exon usage. Our data represent an in-depth profiling of murine primary calvaria osteoblast differentiation by RNA-seq and contribute to our understanding of genetic regulation of this key process in osteoblast biology.

The CDKN2A/B genomic locus is associated with risk of human cancers and metabolic disease. Although the locus contains several important protein-coding genes, studies suggest disease roles for a lesser-known antisense lncRNA encoded at this locus, called ANRIL. ANRIL is a complex gene containing at least 21 exons in simians, with many reported linear and circular isoforms. Like other genes, abundance of ANRIL is regulated by epigenetics, classic transcription regulation, splicing, and post-transcriptional influences such as RNA stability and microRNAs. Known molecular functions of ANRIL include in cis and in trans gene regulation through chromatin modification complexes, and influence over microRNA signaling networks. Polymorphisms at the ANRIL gene are linked to risk for many different cancers, as well as risk of atherosclerotic cardiovascular disease, bone mass, obesity and type 2 diabetes. A broad array of variable reported impacts of polymorphisms on ANRIL abundance, splicing and function suggests that ANRIL has cell-type and context-dependent regulation and actions. In cancer cells, ANRIL gain of function increases proliferation, metastasis, cell survival and epithelial-mesenchymal transformation, whereas ANRIL loss of function decreases tumor size and growth, invasion and metastasis, and increases apoptosis and senescence. In metabolic disease, polymorphisms at the ANRIL gene are linked to risk of type 2 diabetes, coronary artery disease, coronary artery calcium score, myocardial infarction, and stroke. Intriguingly, with the exception of one polymorphism in exon 2 of ANRIL, the single nucleotide polymorphisms (SNPs) associated with atherosclerosis and diabetes are non-overlapping. Evidence suggests that ANRIL gain of function increases atherosclerosis; in diabetes, a risk-SNP reduced the pancreatic beta cell proliferation index. Studies are limited by the uncertain relevance of rodent models to ANRIL studies, since most ANRIL exons do not exist in mouse. Diverse cell-type-dependent results suggest it is necessary to perform studies in the relevant primary human tissue for each disease. Much remains to be learned about the biology of ANRIL in human health and disease; this research area may lead to insight into disease mechanisms and therapeutic approaches.

Epigenetic mechanisms modify gene activity in a stable manner without altering DNA sequence. They participate in the adaptation to the environment, as well as in the pathogenesis of common complex disorders. We provide an overview of the role of epigenetic mechanisms in bone biology and pathology.

Extensive evidence supports the involvement of epigenetic mechanisms (DNA methylation, post-translational modifications of histone tails, and non-coding RNAs) in the differentiation of bone cells and mechanotransduction. A variety of epigenetic abnormalities have been described in patients with osteoporosis, osteoarthritis, and skeletal cancers, but their actual pathogenetic roles are still unclear. A few drugs targeting epigenetic marks have been approved for neoplastic disorders, and many more are being actively investigated. Advances in the field of epigenetics underscore the complex interactions between genetic and environmental factors as determinants of osteoporosis and other common disorders. Likewise, they help to explain the mechanisms by which prenatal and post-natal external factors, from nutrition to psychological stress, impact our body and influence the risk of later disease.

Maternal vitamin D status in pregnancy has been linked to many health outcomes in mother and offspring. A wealth of observational studies have reported on both obstetric outcomes and complications, including pre-eclampsia, gestational diabetes, mode and timing of delivery. Many foetal and childhood outcomes are also linked to vitamin D status, including measures of foetal size, body composition and skeletal mineralization, in addition to later childhood outcomes, such as asthma.

Synthesis of systematic and narrative reviews.

The findings are generally inconsistent in most areas, and, at present, there is a lack of data from high-quality intervention studies to confirm a causal role for vitamin D in these outcomes. In most areas, the evidence tends towards maternal vitamin D being of overall benefit, but often does not reach statistical significance in meta-analyses.

The most conclusive evidence is in the role of maternal vitamin D supplementation in the prevention of neonatal hypocalcaemia; as a consequence the UK department of health recommends that pregnant women take 400 IU vitamin D daily. High-quality randomized placebo-controlled trials, such as the UK-based MAVIDOS trial, will inform the potential efficacy and safety of vitamin D supplementation in pregnancy across a variety of outcomes.

Osteoporosis, the most frequent metabolic disorder of bone, is a complex disease with a multifactorial origin that is influenced by genes and environments. However, the pathogenesis of osteoporosis has not been fully elucidated. The theory of "Developmental Origins of Health and Disease" indicates that early life environment exposure determines the risks of cardiometabolic diseases in adulthood. However, investigations into the effects of maternal nutrition and nutrition exposure during early life on the development of osteoporosis are limited. Recently, emerging evidence has strongly suggested that maternal nutrition has long-term influences on bone metabolism in offspring, and epigenetic modifications maybe the underlying mechanisms of this process. This review aimed to address maternal nutrition and its implications for the developmental origins of osteoporosis in offspring. It is novel in providing a theoretical basis for the early prevention of osteoporosis. Impact statement Our review aimed to address maternal nutrition and its implications for the developmental origins of osteoporosis in offspring, that can novelly provide a theoretical basis for the early prevention of osteoporosis.

Histone deacetylation, DNA methylation, and micro-RNAs (miRNAs) are the three main epigenetic mechanisms that regulate gene expression. All the physiological processes involved in bone remodeling are tightly regulated by epigenetic factors. This review discusses the main epigenetic modifications seen in tumoral and non-tumoral bone diseases, with emphasis on miRNAs. The role for epigenetic modifications of gene expression in the most common bone diseases is illustrated by drawing on the latest publications in the field. In multifactorial bone diseases such as osteoporosis, many epigenetic biomarkers, either alone or in combination, have been associated with bone mineral density or suggested to predict osteoporotic fractures. In addition, treatments designed to modulate bone remodeling by selectively targeting the function of specific miRNAs are being evaluated. Advances in the understanding of epigenetic regulation shed new light on the pathophysiology of other non-tumoral bone diseases, including genetic conditions inherited on a Mendelian basis. Finally, in the area of primary and metastatic bone tumors, the last few years have witnessed considerable progress in elucidating the epigenetic regulation of oncogenesis and its local interactions with bone tissue. These new data may allow the development of epigenetic outcome predictors, which are in very high demand, and of innovative therapeutic agents acting via miRNA modulation.