ReviewDNA methylation and the social gradient of osteoporotic fracture: A conceptual model
Introduction
Osteoporosis is a common skeletal disease that is characterised by microarchitectural deterioration of the bone matrix and depletion of bone mineral density (BMD), with a subsequent increase in risk for fragility fracture [1]. Following a hip fracture, there are many financial, personal and psychosocial outcomes: one in five individuals die within the first year, while 60% of individuals who survive a hip fracture still require assistance to walk one year later, and 33% are totally dependent or are admitted to a nursing home [2], [3]. Osteoporotic fractures accounted for more Disability Adjusted Life Years (DALYs) lost than cancers, with the exception of lung cancer [4]. To advance understanding of the aetiology and pathogenesis of osteoporosis, there are now large-scale efforts to identify genes associated with fracture risk via genome-wide association studies (GWAS) of BMD [5], [6], [7], [8]. The maintenance of BMD is not static, rather osteoblast and osteoclast differentiation processes are highly organized and driven by modifications in gene expression patterns throughout the life course [9]. Indeed, it is argued that the risk of developing osteoporosis occurs over the life course, with potential mechanisms involving epigenetic processes [10]. Epigenetics is the study of alterations in gene expression potential that are not caused by changes in DNA sequence [11]. These processes include DNA methylation (DNAm), histone modification and non-coding RNA (ncRNA) activity [12], with much interest recently directed toward the modulation of epigenetic pathways via DNAm [9]. A seminal review by Delgado-Calle et al [9] argued that DNAm plays a role in the onset and progression of musculoskeletal disorders including osteoporosis; a role similarly reported in other non-communicable diseases such as obesity [13], cancer [14], cardiovascular [15] and metabolic diseases [12], [13]. Furthermore, recent data have suggested that patients with fractures have differentially methylated genes that are related to skeletal development [16]. A role for DNAm in osteoporosis onset is biologically plausible; DNAm not only influences gene expression, but also plays a role in establishing a bone cell phenotype. Furthermore, DNAm is involved in the regulation of osteogenic differentiation of mesenchymal cells [17], and epigenetic mechanisms (one of which is DNAm) are important for osteoclast differentiation [18].
There is emerging interest in the role that social factors may play in influencing DNAm. For instance, in a study of 92 Canadian adults (aged 24-45 years; 62% female) socioeconomic position (SEP) during early life, defined as parental occupation (manual vs. non-manual), showed associations with DNAm in later life [19]. Similar associations were observed in a larger study of 239 adults (aged 35-64 years; 51% female) from the United Kingdom (UK), where SEP during adulthood was defined as residing in an affluent vs. deprived area [20]. In a study of 89 women (aged 38-46 years) from the United States of America (USA) low income at birth, being raised in a single parent family, and lower adult educational attainment were all associated with higher DNAm profiles in adulthood [21]. Those observations are supported by evidence from a rhesus macaque model, which showed that dominance-rank, an indicator of social hierarchy and thus a proxy for SEP, was associated with differences in levels of chronic stress and the subsequent modulation of physiological responses and DNAm profiles [22]. The available studies indicate plasticity in molecular responses in stress response pathways might be related to the influence of SEP on the epigenetic pathway/s. However, conflicting data also exist: a study of 85 women from the USA found no association between SEP (an aggregate measure derived from maternal and paternal education, occupation and income at birth and at 7 years of age), and DNAm [23]. Nevertheless, an association between the allostatic load (the cumulative dysregulation of biological systems [24]) and SEP has been reported in some [25], although not all [26], reviews.
The public health importance of the social gradient of osteoporosis is underscored by increased attention in recent years [27], [28], [29], [30]. Yet, the underlying mechanism for that gradient remains uncertain. The epigenetic signature is influenced by a multitude of environmental factors across the lifespan, and the epigenome appears to function as a vital conduit that transduces exposures into phenotypic expression and disease risk [15], [31]. We suggest that understanding this mechanism with respect to specific social determinants may identify various entry points for interventions in order to reduce the prevalence of osteoporosis and, consequently, reduce the social gradient of osteoporotic fracture [27]. This paper proposes a conceptual model, based on the challenge posed by social disadvantage to achieving allostasis (the maintenance of stability, or homeostasis, through change [24]), and the ‘three-hit theory’ of the allostatic load model as identified by McEwen et al [32], and later expanded upon by Daskalakis et al [33], whereby genetic predisposition provides the first ‘hit’ to allostasis, the early life environment provides the second, and later life environment provides the third. Our proposed model posits why socially disadvantaged individuals may be at greater predisposition for increased risk of osteoporotic fracture compared to their more advantaged counterparts, and explores the modulation across the life course of the epigenetic signature. We argue that epigenetic mechanisms such as DNAm are highly influenced by SEP, and that social determinants are dynamic modulators of gene expression with relevance to the field of osteoporosis.
Section snippets
In utero
In addition to non-modifiable genetic predisposition (including sex and ethnicity [34]; see Fig. 1, Box 1), mechanisms have been proposed to explain epigenetic influences that occur in utero and which impact adult bone health later in life.
Recent research has demonstrated that foetal under-nutrition, indicated by low birth weight, is associated not only with adverse childhood outcomes such as stunting and reduced cognitive function, but also with increased morbidity in adult life from
Conclusion
Taking the emerging evidence-base in context, cumulative stressors, responses to stressors, a heightened inflammatory state and subsequent increase in osteoporotic fracture risk are all influenced by SEP. Whilst factors such as physical activity and nutrition exert direct biological effects on bone, and are associated with DNAm status, the recognised social gradient of risk factors for osteoporosis also act via epigenetic-mediated dysregulation of inflammation. More specifically, relationships
Conflict of interest
Sharon Brennan-Olsen, Richard Page, Michael Berk, José Riancho, William Leslie, Scott Wilson, Karen Saban, Linda Janusek, Julie Pasco, Jason Hodge, Shae Quirk, Natalie Hyde, Sarah Hosking, and Lana Williams declare that they have no conflict of interest.
Acknowledgements/Funding
SLB-O is supported by an Alfred Deakin Postdoctoral Fellowship (2015-16). JAR is supported by Instituto de Salud Carlos III (PI12/615). LJW is supported by a National Health and Medical Research Council (NHMRC of Australia) Career Development Fellowship (2015-18). NKH is supported by an Australian Postgraduate Award, Deakin University (2013-16). MB is supported by a NHMRC Senior Principal Research Fellowship (1059660). SEQ is supported by a NHMRC Public Health and Health Services Research
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