title: DNA methylation and the social gradient of osteoporotic fracture: A conceptual model.
abstract: BACKGROUND
  Although there is a documented social gradient for osteoporosis, the underlying mechanism(s) for that gradient remain unknown. We propose a conceptual model based upon the allostatic load theory, to suggest how DNA methylation (DNAm) might underpin the social gradient in osteoporosis and fracture. We hypothesise that social disadvantage is associated with priming of inflammatory pathways mediated by epigenetic modification that leads to an enhanced state of inflammatory reactivity and oxidative stress, and thus places socially disadvantaged individuals at greater risk of osteoporotic fracture.
  
  
  RESULTS
  Based on a review of the literature, we present a conceptual model in which social disadvantage increases stress throughout the lifespan, and engenders a proinflammatory epigenetic signature, leading to a heightened inflammatory state that increases risk for osteoporotic fracture in disadvantaged groups that are chronically stressed.
  
  
  CONCLUSIONS
  Our model proposes that, in addition to the direct biological effects exerted on bone by factors such as physical activity and nutrition, the recognised socially patterned risk factors for osteoporosis also act via epigenetic-mediated dysregulation of inflammation. DNAm is a dynamic modulator of gene expression with considerable relevance to the field of osteoporosis. Elucidating the extent to which this epigenetic mechanism transduces the psycho-social environment to increase the risk of osteoporotic fracture may yield novel entry points for intervention that can be used to reduce individual and population-wide risks for osteoporotic fracture. Specifically, an epigenetic evidence-base may strengthen the importance of lifestyle modification and stress reduction programs, and help to reduce health inequities across social groups.
  
  
  CONCLUSIONS
  Our conceptual model proposes how DNA methylation might underpin the social gradient in osteoporotic fracture. We suggest that social disadvantage is associated with priming of inflammatory signalling pathways, which is mediated by epigenetic modifications, leading to a chronically heightened inflammatory state that places disadvantaged individuals at greater risk of osteoporosis.
authors.affiliation: IMPACT Strategic Research Centre, School of Medicine, Deakin University, C/- Barwon Health, Ryrie Street, Geelong, 3220, VIC, Australia; Australian Institute for Musculoskeletal Sciences, The University of Melbourne, C/- Sunshine Hospital, Furlong Road, Melbourne, 3021, VIC, Australia; Institute for Health and Ageing, Australian Catholic University, Melbourne, 3000, VIC, Australia. Electronic address: sharob@barwonhealth.org.au.
authors.forename: Sharon L
authors.initials: SL
authors.lastname: Brennan-Olsen
authors.affiliation: IMPACT Strategic Research Centre, School of Medicine, Deakin University, C/- Barwon Health, Ryrie Street, Geelong, 3220, VIC, Australia; Barwon Orthopaedic Research Unit, Barwon Health, Geelong, 3220, VIC, Australia.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Page
authors.affiliation: IMPACT Strategic Research Centre, School of Medicine, Deakin University, C/- Barwon Health, Ryrie Street, Geelong, 3220, VIC, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Berk
authors.affiliation: Department of Internal Medicine, Valdecilla Research Institute (IDIVAL), University of Cantabria, Santander, Spain.
authors.forename: José A
authors.initials: JA
authors.lastname: Riancho
authors.affiliation: Department of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: William D
authors.initials: WD
authors.lastname: Leslie
authors.affiliation: Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, 6009, Australia; School of Medicine and Pharmacology, The University of Western Australia, Nedlands, 6009, WA, Australia; Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
authors.forename: Scott G
authors.initials: SG
authors.lastname: Wilson
authors.affiliation: Marcella Niehoff School of Nursing, Loyola University Chicago, Maywood, IL, USA; Centre of Innovation for Complex Chronic Healthcare, Edward Hines Jr. VA Hospital, Hines, IL, USA.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Saban
authors.affiliation: Marcella Niehoff School of Nursing, Loyola University Chicago, Maywood, IL, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: Janusek
authors.affiliation: IMPACT Strategic Research Centre, School of Medicine, Deakin University, C/- Barwon Health, Ryrie Street, Geelong, 3220, VIC, Australia.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Pasco
authors.affiliation: IMPACT Strategic Research Centre, School of Medicine, Deakin University, C/- Barwon Health, Ryrie Street, Geelong, 3220, VIC, Australia.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Hodge
authors.affiliation: IMPACT Strategic Research Centre, School of Medicine, Deakin University, C/- Barwon Health, Ryrie Street, Geelong, 3220, VIC, Australia.
authors.forename: Shae E
authors.initials: SE
authors.lastname: Quirk
authors.affiliation: IMPACT Strategic Research Centre, School of Medicine, Deakin University, C/- Barwon Health, Ryrie Street, Geelong, 3220, VIC, Australia.
authors.forename: Natalie K
authors.initials: NK
authors.lastname: Hyde
authors.affiliation: IMPACT Strategic Research Centre, School of Medicine, Deakin University, C/- Barwon Health, Ryrie Street, Geelong, 3220, VIC, Australia.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Hosking
authors.affiliation: IMPACT Strategic Research Centre, School of Medicine, Deakin University, C/- Barwon Health, Ryrie Street, Geelong, 3220, VIC, Australia.
authors.forename: Lana J
authors.initials: LJ
authors.lastname: Williams
mesh_terms: D000375:Aging / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D044127:Epigenesis, Genetic; D006801:Humans; D008954:Models, Biological; D058866:Osteoporotic Fractures / Q000235:genetics*; D012959:Socioeconomic Factors
keywords: DNA methylation; epigenetic; fracture; life course; osteoporosis; social gradient