Introduction
-
outline some anthropometric findings for AIS girls not explained by prevailing theories of pathogenesis;
-
provide a novel theoretical framework for AIS pathogenesis in girls to explain the findings and connect knowledge from several biological fields;
-
suggest tests of the theory including endocrine studies;
-
focus on therapeutic implications and some possible manipulatable causes;
-
consider an evolutionary perspective [53] for the pathogenesis of AIS in girls stemming from female fat accumulation in puberty; and
-
foster new thinking and research to improve causal knowledge of AIS pathogenesis.
Background
General comments
Biomechanical spinal growth modulation
Neurological abnormalities
Origins of the double neuro-osseous theory - the escalator concept
Origins of the double neuro-osseous theory - the LHS concept
Scientific Basis of the Escalator Concept
The central nervous system and the changes of the human frame during development and growth
CNS body schema ('body-in-the-brain')
SOMATIC NERVOUS SYSTEM - the escalator concept
Normal adolescent girls
Girls with AIS
Postural scoliosis in melatonin-deficient mice
Some Observations on Skeletal Maturation Relating to AIS not Explained by Pathogenetic Theories (Appendix 1, Items 1-15)
Prescoliotics and early skeletal maturation of AIS subjects
-
Early radiological maturation at 11-12 years of age in AIS subjects [137].
-
Early adolescent skeletal growth attained for age by AIS girls [38, 39, 41, 121, 135‐141]. In the preoperative AIS girls of the relatively higher BMI subset, all the skeletal parameters we measured when plotted as standard deviation scores against age, showed negative regressions - several statistically significant, but not for the lower BMI subset of preoperative AIS girls (unpublished observations).
Extra-spinal skeletal length asymmetries detected with AIS
Body Mass Index (BMI) Relating to AIS and Causal Genes
BMI and AIS
Overweight AIS patients
Fat mass related to bone mass and genetic markers in normal children
Fto gene in mice
Relation of relatively higher and lower BMIs to skeletal sizes and asymmetries in AIS girls
Body Mass Index (BMI) Subsets in AIS and Normal Girls Reveal Effects of Energy Stores on Skeletal Maturation, Asymmetry and Overgrowth: Summary of Recent Findings
-
"Energy", is used because relatively higher BMI probably implies relatively higher circulating leptin indicating more energy available from fat.
-
"Priority", is used because growth plates (GPs) contributing to the trunk width of girls, take priority over those in limbs in "tapping" available energy.(1)How does the higher BMI subset of preoperative girls attain greater biiliac width for age than the lower BMI subset? The earlier menarcheal age of the higher BMI subset with earlier puberty suggests hormonal effects cause earlier iliac maturation with relative overgrowth of younger AIS girls.(2)Why is this BMI-related earlier maturation of trunk widths - biiliac, chest and biacromial in girls scarcely found in the limb lengths of girls? (Figure 5). The growth plates in trunk and limbs may respond -
-
intrinsically and differently to hormones by genetic programs established in early embryogenesis, and/or
-
extrinsically in the presence of any sympathetic nervous system innervation (see Autonomic nervous system - leptin-hypothalamic-sympathetic nervous system (LHS)-driven mechanism in health and LHS concept in AIS).
-
Energy priority of trunk length growth in leptin-deficient mice?
Skeletal asymmetries
Mean upper arm length asymmetries in preoperative girls
Right thoracic AIS, curve severity and upper arm length asymmetries
Right thoracic AIS, upper arm length asymmetry and age
Skeletal overgrowth for age in preoperative AIS/normal girls (Figure 7)
Back contour asymmetry in normal girls and boys
Considered together, the above findings are not explained by any of the prevailing theories of AIS pathogenesis (Appendix 1, items 1-15)
Scientific Basis of Leptin-Hypothalamic-Sympathetic Nervous System (LHS) Concept
Thoraco-spinal concept
New neuroskeletal biology (Figure 8)
Energy homeostasis and sympathetic nervous system (Figure 8)
White adipose tissue, leptin, hypothalamus, sympathetic nervous system and bone formation/resorption in health (Figure 8)
Leptin and bone growth in mice (Figures 8 and 9)
Leptin and bone growth in children
Leptin, hypothalamus and AIS
Central leptin resistance in obesity and possibly in healthy females
Hypothalamic mechanisms of central leptin resistance in obesity
AIS as a systemic disorder - platelet calmodulin dysfunction [21, 22, 107]
AIS as a systemic disorder - melatonin, melatonin-signaling, osteopontin and soluble CD44 receptor
Melatonin deficiency
Systemic melatonin-signaling dysfunction
Osteopontin and soluble CD44 receptor
-
patients with idiopathic scoliosis, correlating significantly with curve severity, and
-
"an asymptomatic at-risk group" (offspring born from at least one scoliotic parent).
Some melatonin-deficient mouse models of scoliosis - markers of developmental stress?
Osteopontin and bone remodeling in mice
Melatonin receptor 1B (MT1B), AIS, glucose metabolism and type 2 diabetes
-
are consistent with hormone receptors having a variety of parallel but independent downstream effects; and
-
raise the question: Do post-operative AIS girls after 60 years of age have a lower prevalence of type 2 diabetes, because they are protected by being leaner and using their energy in a different way with a more efficient burn within their systemic disorder?
AUTONOMIC NERVOUS SYSTEM - leptin-hypothalamic-sympathetic nervous system (LHS)-driven mechanism in health and LHS concept in AIS (Figures 1, 4 and 5)
Trunk widening in normal adolescent girls and the putative LHS-driven mechanism
-
modified spinal movements [275], and in the last 3 million years -
The LHS concept for girls with AIS
Central leptin resistance/sensitivity and the LHS concept for AIS pathogenesis in girls
Autonomic Nervous System - Possible Factors Causing Selective Hypothalamic Up-Regulation in AIS
G-protein coupled receptors
Circulating osteopontin (OPN)
Inhibitory molecules in the JAK/STAT pathway
Stimulatory molecules in the PI 3 kinase pathway
Hormesis - the putative cause of asymmetry in the LHS concept for AIS
Autonomic Nervous System - Rett and Prader-Willi Syndromes
Rett syndrome
Prader-Willi syndrome (PWS)
Evolutionary Origins
Melatonin decrease - the turning point of human evolution?
Fat - Brain Growth and Nutritional Stresses
Fat - Trunk Width Growth and the LHS Normal Mechanism
-
Pelvic width. In hominins, increased pelvic as iliac and sacral width for habitual erect walking was established by about 3 mya (Figure 12).
-
Thorax and shoulder gitrdle width. Ribcage widening, particularly of the upper thorax (Figure 11) happened in the last 3 million years. The wide shoulders characteristic of Homo[303] evidently resulted from upper ribcage widening relative to depth (Figures 10 and 11), with clavicular lengthening (Figure 14). This trunk widening at the shoulder girdles is likely to have been selected by:a)the evolution of upright posture giving an enhanced respiratory importance to the upper thorax [see [268]]; and
-
pelvic widening mainly from sacral widening, enabling bipedalism with upright posture, later
-
upper thorax with shoulder widening, and still later
-
increased pelvic depth of Homo sapiens (Figure 12).
-
In evolution, to reduce toxicity to the hypothalamus of the raised circulating leptin levels - signaling greater adipose tissue stores particularly in females, hypothalamic sensitivity to circulating leptin became diminished (desensitized, or down-regulated, i.e. central leptin resistance), possibly involving increased action of inhibitory molecules such as SOCS-3 and PTP-1B, or decreased action of stimulatory molecules such as SH2B1. It needs to be established whether humans deal with SOCS-3, PTP-1B, and SH2B1 differently from other apes.
-
In evolution, the development of human bipedalism and upright posture necessitated adaptations of postural control by the somatic nervous system [51].
Fat - AIS in Girls and the LHS Concept of Pathogenesis
Endocrine and Therapeutic Implications
Hypothalamus
Neuroendocrinogy
Sympathetic nervous system and GH/IGF axis
GH treatment and the Prader-Willi syndrome (PWS)
Sex hormones
Estrogen and testosterone
Gonadorhelin analogues
Ballet dancers, hypoestrogenism and leptin
Melatonin-signaling dysfunction [12‐17]
Research needs
Discussion
Abnormalities revealed by higher and lower BMI subsets for AIS girls
Skeletal sizes for age - curve severity, sympathoactivation and hormonal stimulation
Medical conditions showing inverse relation of GH/IGF axis secretion and sympathoactivation
Skeletal asymmetries and lower BMI subsets
Upper arm length asymmetry and the higher BMI subset of right thoracic AIS
Explanations for undisputed facts about AIS
Testing the Theory
-
the funnel-shaped upper chest in progressive IIS [400];
Conclusion
-
Sympathoactivation expressed asymmetrically in vertebral plates - left-right, front-back and/or torsionally - and in some paired bones.
-
Hormonal effects cause exaggeration of the sympathetic-induced vertebral/rib asymmetry(ies) contributing to progression of larger (preoperative) AIS curves in girls.
-
Curve progression is postulated to involve an inverse relation of sympathoactivation and GH/IGF secretions (Figure 5). An inverse relation of these functions is found in several medical conditions.
-
white adipose tissue, the adiposity hormone leptin secreted by adipose tissue which functions as a sentinel of energy balance and long-term adiposity to the hypothalamus; and
-
central leptin resistance in obesity and possibly in healthy females.