Adolescent idiopathic scoliosis (AIS), environment, exposome and epigenetics: a molecular perspective of postnatal normal spinal growth and the etiopathogenesis of AIS with consideration of a network approach and possible implications for medical therapy

Abstract

Genetic factors are believed to play an important role in the etiology of adolescent idiopathic scoliosis (AIS). Discordant findings for monozygotic (MZ) twins with AIS show that environmental factors including different intrauterine environments are important in etiology, but what these environmental factors may be is unknown. Recent evidence for common chronic non-communicable diseases suggests epigenetic differences may underlie MZ twin discordance, and be the link between environmental factors and phenotypic differences. DNA methylation is one important epigenetic mechanism operating at the interface between genome and environment to regulate phenotypic plasticity with a complex regulation across the genome during the first decade of life. The word exposome refers to the totality of environmental exposures from conception onwards, comprising factors in external and internal environments. The word exposome is used here also in relation to physiologic and etiopathogenetic factors that affect normal spinal growth and may induce the deformity of AIS. In normal postnatal spinal growth we propose a new term and concept, physiologic growth-plate exposome for the normal processes particularly of the internal environments that may have epigenetic effects on growth plates of vertebrae. In AIS, we propose a new term and concept pathophysiologic scoliogenic exposome for the abnormal processes in molecular pathways particularly of the internal environment currently expressed as etiopathogenetic hypotheses; these are suggested to have deforming effects on the growth plates of vertebrae at cell, tissue, structure and/or organ levels that are considered to be epigenetic. New research is required for chromatin modifications including DNA methylation in AIS subjects and vertebral growth plates excised at surgery. In addition, consideration is needed for a possible network approach to etiopathogenesis by constructing AIS diseasomes. These approaches may lead through screening, genetic, epigenetic, biochemical, metabolic phenotypes and pharmacogenomic research to identify susceptible individuals at risk and modulate abnormal molecular pathways of AIS. The potential of epigenetic-based medical therapy for AIS cannot be assessed at present, and must await new research derived from the evaluation of epigenetic concepts of spinal growth in health and deformity. The tenets outlined here for AIS are applicable to other musculoskeletal growth disorders including infantile and juvenile idiopathic scoliosis.

Microarray expression profiling identifies genes with altered expression in Adolescent Idiopathic Scoliosis

“…Interestingly, patients with AIS with similar gene profiles may have varying severity of spinal curve suggesting that genetic factors likely control disease susceptibility and course, but not disease pattern. Hormonal and environmental factors may also affect the clinical phenotype and the severity of curve [29] although patients may have the similar gene profiles but this area remains unexplored and beyond the scope of this study. Taken together our study revealed gene expression changes in AIS osteoblasts.…”

Participation of sex hormones in multifactorial pathogenesis of adolescent idiopathic scoliosis

“…This spinal deformation occurs mostly among pubescent girls [4]. Many authors emphasize multifactorial pathomechanism of scoliosis [5][6][7][8], and the involvement of genetic and epigenetic predispositions, and the influence of hormonal factors are widely accepted [6,7,[9][10][11][12][13][14][15].…”

“…It is postulated that the development of AIS comprises of two stages: initial functional impairment of osteoblasts and osteoclasts, and the stage of actual spinal deformation [6,10]. The reasons for the above mentioned pathological changes are still a subject of research.…”

Factors Associated With Scoliosis in Schoolchildren: a Cross-Sectional Population-Based Study

“…The epigenetic effects mainly occur through DNA methylation in the first decade of life, due to internal and external environment exposure. 3 …”