Research Progress on the Etiology and Pathogenesis of Adolescent Idiopathic Scoliosis
Adolescent idiopathic scoliosis (AIS) is a complex three-dimensional spinal deformity that typically develops during early adolescence, between the ages of 11 and 18 years. It is the most common form of idiopathic scoliosis in children, with a global prevalence ranging from 0.47% to 5.20%. In China, the incidence of scoliosis varies from 0.6% to 2.0%, with AIS accounting for 90% of these cases. The prevalence of AIS is higher in girls, with a reported rate of 2.4% in China.
The etiology and pathogenesis of AIS remain unclear, despite extensive research. This review categorizes the existing theories and hypotheses into nine aspects: bone marrow mesenchymal stem cell studies, genetic studies, tissue analysis, spine biomechanics measurements, neurologic analysis, hormone studies, biochemical analysis, environmental factor analysis, and lifestyle explorations. These categories provide a comprehensive framework for understanding the multifactorial nature of AIS and offer guidance for future research and treatment strategies.
Bone Marrow-Derived Mesenchymal Stem Cells (BM-MSCs) play a crucial role in the pathogenesis of AIS. BM-MSCs have the potential to differentiate into osteoblasts, chondrocytes, or adipocytes. Studies have shown that AIS patients exhibit decreased osteogenic ability and a tendency towards adipogenic differentiation in MSCs, leading to low bone mineral density (BMD). Proteomic analysis of MSCs from AIS patients revealed alterations in bone growth-related proteins, including pyruvate kinase M2 (PKM2), annexin A2, heat shock 27 k protein (HSP27), g-actin, and b-actin. These changes are associated with diminished ossification and low bone mass. Additionally, microarray and pathway analysis identified differentially expressed genes that inhibit osteogenic differentiation and affect bone formation. Melatonin receptors and leptin receptors in AIS MSCs are down-regulated, reducing their response to melatonin and leptin, which are essential for bone formation. Epigenetic studies have also identified long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) that regulate gene expression and osteogenic differentiation in AIS patients.
Genetic studies have provided significant insights into the pathogenesis of AIS. Twin studies have shown a higher concordance rate in monozygotic pairs compared to dizygotic pairs, indicating a genetic component. Genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) associated with AIS. Genes such as MAPK7, LBX1, GPR126, and TGFB1 have been implicated in AIS development. Epigenetic changes, including DNA methylation and non-coding RNAs, also play a role in regulating gene expression and contributing to AIS.
Tissue analysis has revealed abnormalities in bone and muscle tissues of AIS patients. Histological studies have shown sub-normal bone volume and high bone turnover rates in the spinous process of AIS patients. Paravertebral muscles in AIS patients exhibit alterations in fiber type composition and contractility, which may contribute to spinal deformity. Genetic variants in FBN1 and FBN2 have been associated with curve progression and up-regulation of the TGF-b signaling pathway in paravertebral muscles.
Spine biomechanics studies have focused on relative anterior spinal overgrowth (RASO) and the role of intervertebral discs in AIS development. RASO, characterized by accelerated growth of the anterior column relative to the posterior column, has been linked to spinal deformity. Finite element models have demonstrated that RASO can lead to scoliotic progression. Intervertebral discs also contribute to spinal asymmetry, with disc wedging being a significant factor in the early stages of AIS. Biomechanical interactions between the spine and other parts of the torso, such as rib length asymmetry and handedness, have also been explored.
Neurologic analysis has investigated the association between brain abnormalities and AIS. Magnetic resonance imaging (MRI) studies have shown white matter attenuation and cortical thickness differences in AIS patients, particularly in regions involved in motor and vestibular function. Cerebellar abnormalities, including tonsillar ectopia and regional volume enlargement, have been observed in AIS patients and may contribute to functional impairments. Vestibular system deficits have also been implicated in AIS, with studies showing lateral semicircular canal asymmetry and verticality perception disorders in AIS patients.
Hormone studies have explored the role of melatonin, calmodulin, leptin, estrogen, and growth hormone in AIS pathogenesis. Melatonin deficiency and disturbed biorhythm have been associated with AIS, with reduced melatonin receptor expression in osteoblasts and growth plate chondrocytes. Calmodulin, a secondary messenger involved in muscle function and bone formation, has been found to be imbalanced in AIS patients. Leptin, which regulates bone formation, has been shown to be down-regulated in AIS patients, contributing to low BMD. Estrogen and growth hormone also play roles in bone maturation and skeletal growth, with alterations in their expression and function linked to AIS development.
Biochemical analysis has identified disruptions in bone mineral metabolism, vitamin D, and lipid metabolism in AIS patients. Imbalance in the RANKL/OPG system, which regulates bone resorption, has been associated with low BMD in AIS. Vitamin D receptor gene polymorphisms and altered lipid metabolism profiles have also been implicated in AIS. Biochemical changes in scoliotic discs, such as shifts in glycosaminoglycan distribution and increased collagen expression, may contribute to disc degeneration and curve progression.
Environmental and lifestyle factors have been investigated as potential contributors to AIS. High environmental selenium levels have been associated with spinal neuro-osseous growth and tethering, leading to spinal curvature. Chlorine exposure from indoor swimming pools has been hypothesized to have neurotoxic effects that induce AIS. Gut microbiome alterations have been linked to plasma proteome changes in AIS patients, with certain microbial abundances correlating with curve severity. Physical activities, such as ballet training and reduced participation in sports, have been associated with AIS risk.
An integrated theory, the double neuro-osseous theory, proposes that AIS results from a developmental disharmony between the autonomic and somatic nervous systems, exacerbated by hormonal and genetic factors. This theory suggests that leptin-hypothalamic-sympathetic nervous system interactions and somatic nervous system dysfunction contribute to spinal deformity and skeletal overgrowth in AIS.
In conclusion, AIS is a multifactorial disease with intrinsic and extrinsic alterations contributing to its pathogenesis. Bone formation abnormalities appear to be a central aspect of AIS etiology, with genetic, hormonal, biochemical, and environmental factors all playing roles. Further research is needed to clarify the controversial aspects of AIS pathogenesis and integrate existing theories to develop effective prevention and treatment strategies.
doi.org/10.1097/CM9.0000000000000652
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