Sphingosine 1-phosphate differentially regulates proliferation of C2C12 reserve cells and myoblasts

Scoliosis is a condition that involves an abnormal curvature and deformity of the spinal vertebrae. The genetic background and key gene for congenital scoliosis in humans are still poorly understood. Ishibashi rats (ISR) have congenital malformation of the lumbar vertebrae leading to kyphoscoliosis similar to that seen in humans. To understand the pathogenesis of congenital scoliosis, we have studied the abnormality of vertebral formation and the associated gene expression in ISR. Almost all ISR showed kyphosis or scoliosis of the lumbar vertebrae. In ISR with severe kyphosis, some vertebral disks were missing and some vertebral bodies were fused. Of the ISR, 27% showed hemi-lumbarization of lumbar and sacral vertebrae. Homeotic transformation of the first sacral vertebra into the seventh lumbar vertebra and the resultant loss of the fourth sacral vertebra were seen in half of the ISR. We also found unilateral fusions and deformities of primary ossification centers of the lumbar vertebral column in fetal ISR. Moreover, we observed that the expression levels of Hox10 and Hox11 paralogs in lumbo-sacral transitional areas of ISR were extremely low compared with those of normal rats. These results suggest that fusion of primary ossification centers in lumbar vertebrae in the embryonic period causes scoliosis and kyphosis and that Hox genes are involved in the occurrence of homeotic transformation in lumbo-sacral vertebrae of congenital kyphoscoliotic ISR.     

Aetiology of skeletal deformities in the Zebra Danio fish (Bruchydanio rerio, Hamilton-Buchanan)

Laboratory bred Zebra Danio ( Brachydanio rerio , Hamilton-Buchanan) tropical fish are prone to skeletal deformities resembling scoliosis and lordosis. This condition appears related to diet and has been studied by breeding from different broods of fish for three generations. Two broods bred using two commercially available tropical flaked foods developed severe spinal curvature three to six weeks post-hatching. A third brood of fish fed exclusively on live food did not develop any deformity. The results demonstrate that a dietary factor is responsible for the deformities and that the Zebra Danio is especially susceptible to this factor as other species breed normally when fed the same commercial diet. Analysis of the diets showed no deficiency in either ascorbic acid (Vitamin C) or tryptophan, deficiency of either being associated with scoliosis and lordosis in fish. The analysis did show, however, a relationship between the lead content of the diet and the incidence of deformities. Lead has previously been implicated in skeletal deformities in second and third generation Brook trout, Salvelinus fontinalis.     

Brace technology thematic series: the dynamic derotation brace

Background

The curveback lineage of guppy is characterized by heritable idiopathic-type spinal curvature that develops during growth. Prior work has revealed several important developmental similarities to the human idiopathic scoliosis (IS) syndrome. In this study we investigate structural and histological aspects of the vertebrae that are associated with spinal curvature in the curveback guppy and test for sexual dimorphism that might explain a female bias for severe curve magnitudes in the population.

Methods

Vertebrae were studied from whole-mount skeletal specimens of curved and non-curved adult males and females. A series of ratios were used to characterize structural aspects of each vertebra. A three-way analysis of variance tested for effects of sex, curvature, vertebral position along the spine, and all 2-way interactions (i.e., sex and curvature, sex and vertebra position, and vertebra position and curvature). Histological analyses were used to characterize micro-architectural changes in affected vertebrae and the intervertebral region.

Results

In curveback, vertebrae that are associated with curvature demonstrate asymmetric shape distortion, migration of the intervertebral ligament, and vertebral thickening on the concave side of curvature. There is sexual dimorphism among curved individuals such that for several vertebrae, females have more slender vertebrae than do males. Also, in the region of the spine where lordosis typically occurs, curved and non-curved females have a reduced width at the middle of their vertebrae, relative to males.

Conclusions

Based on similarities to human spinal curvatures and to animals with induced curves, the concave-convex biases described in the guppy suggest that there is a mechanical component to curve pathogenesis in curveback. Because idiopathic-type curvature in curveback is primarily a sagittal deformity, it is structurally more similar to Scheuermann kyphosis than IS. Anatomical differences between teleosts and humans make direct biomechanical comparisons difficult. However, study of basic biological systems involved in idiopathic-type spinal curvature in curveback may provide insight into the relationship between a predisposing aetiology, growth, and biomechanics. Further work is needed to clarify whether observed sex differences in vertebral characteristics are related to the female bias for severe curves that is observed in the population.     

Use of Neural Networks to Correlate Spine and Rib Deformity in Scoliosis

Artificial neural networks (ANN's) recognize patterns relating input and output data in a manner analogous to the function of biological neurons. Here, we show that ANN's can predict rib deformity in scoliosis more accurately than regression analysis. ANN's and linear regression models were developed to predict rib rotation from several combinations of input spinal indices including Cobb angle, vertebral rotation, apex location and orientation of the plane of maximal curvature. ANN's averaged 60% correct predictions compared to 34% for regression analysis. This study provides evidence for the utility of artificial neural networks in scoliosis research. These data lend credence to the use of ANN's in future work on the prediction of scoliotic spinal deformity from torso surface data, which would permit assessment of scoliosis severity with minimal use of harmful X-rays.     

Preliminary studies of neurosensory and cardiopulmonary health compromise in captive- bred Rhesus macaques (Macaca mulatta) suffering scoliosis

Background It has been widely documented that quadrupedal animals rarely display natural spontaneous scoliotic rachis deviations of the spinal column. The objective was to determine spinal deformities developed by geriatric monkeys of the Macaca mulatta species, by radiographical and tomographical studies of the vertebral column correlating morphological changes with altered physiological parameters and electrical neurosensorial conductivity of somatosensory‐evoked potentials (SEPs). Materials and methods A cohort of six geriatric monkeys was used: three non‐scoliotic subjects and three monkeys with naturally acquired true scoliosis. Results Radiographic and tomographic studies depicted a thoracic curvature displaying a left‐sided thoracic vertebral rotation. The evaluation of physiological parameters demonstrated significant differences in the respiratory rate, as it was observed for the diastolic blood pressures, which showed a decrease in the monkeys with scoliosis compared with healthy monkeys. Regarding the SEPs studies, the non‐parametric test for independent samples Mann–Whitney U test displayed a significant difference observed at the left and right thoracic derivative in P1; while regarding the study of upper limbs, a significant difference was seen at the Erb’s point derivative, left afferency in P1, showing in all the derivatives an increase in latency in monkeys with scoliosis versus monkeys in the control group. Conclusions This study has demonstrated that quadrupedal animals can develop true scoliosis showing an analogous way to that occurring in humans.     

Use of Neural Networks to Correlate Spine and Rib Deformity in Scoliosis

Abstract

Artificial neural networks (ANN's) recognize patterns relating input and output data in a manner analogous to the function of biological neurons. Here, we show that ANN's can predict rib deformity in scoliosis more accurately than regression analysis. ANN's and linear regression models were developed to predict rib rotation from several combinations of input spinal indices including Cobb angle, vertebral rotation, apex location and orientation of the plane of maximal curvature. ANN's averaged 60% correct predictions compared to 34% for regression analysis. This study provides evidence for the utility of artificial neural networks in scoliosis research. These data lend credence to the use of ANN's in future work on the prediction of scoliotic spinal deformity from torso surface data, which would permit assessment of scoliosis severity with minimal use of harmful X-rays.     

Effects of phosphorus and vitamin C deficiency,vitamin A toxicity,and lipid peroxidation on skeletal abnormalities in Atlantic halibut (Hippoglossus hippoglossus)

Dietary nutrients play an important role in skeletal tissue metabolism of fish. Deficiency and toxicity of certain nutrients have been linked to bone deformities in larval and juvenile fish. The pathogenesis of skeletal disorders in larval and juvenile fish from the same genetic stock, cultured under similar environment conditions is often difficult to distinguish when marginal deficiencies of multiple nutrients are involved. A study was conducted to characterize the skeletal deformities linked to the deficiency of phosphorus and ascorbic acid, vitamin A toxicity and lipid peroxidation in juvenile halibut. Five experimental diets containing a low level of phosphorus (0.5% dry matter basis), no vitamin C supplement, high level of vitamin A (80 000 IU kg^?1) and oxidized marine fish oil (peroxide value, 7.53 meq kg^?1) and a control diet based on cod fillet and vitamin free casein were fed to juvenile Atlantic halibut for 14 weeks in an attempt to characterize the skeletal deformities. Phosphorus, ascorbic acid, retinol, and α‐tocopherol concentrations of liver and kidney were measured at 0 and 14 weeks. Reduced vertebral ash and phosphorus content were observed in fish fed the low phosphorus diet. Skeletal abnormalities included abnormal hemal and neural spines in the hemal region and scoliosis in the cephalic and hemal regions of the vertebral column. Hepatic and kidney ascorbic acid concentrations were significantly lower in the group fed no ascorbic acid supplement. Skeletal abnormalities were scoliosis and lordosis primarily in the hemal region of the vertebral column. High levels of vitamin A in the diet caused increased hepatic retinol content and scoliosis spanning the cephalic/prehemal and anterior hemal regions of the vertebral column. Fish fed the oxidized oil diet showed increased thiobarbituric acid (TBA) value in the liver and muscle tissue with no significant decrease in hepatic vitamin E concentration. The most frequent skeletal deformity observed was scoliosis, spanning the cephalic/prehemal regions as well as the anterior hemal region of the vertebral column. The pattern and type of abnormalities observed in fish fed these experimental diets were similar to those observed in a commercial halibut hatchery.     

Emerging roles of non‐coding RNAs in scoliosis

Scoliosis, a complex three‐dimensional deformity of the spine with the Cobb angle (a measure of the spinal lateral curvature) >10 degree, encompasses a spectrum of pathologies, including congenital, idiopathic, syndromic and neuromuscular aetiologies. The pathogenesis is multifactorial involving both environmental and genetic factors but the exact cellular and molecular mechanisms of disease development remain largely unknown. Emerging evidence showed that non‐coding RNAs (ncRNAs), namely microRNAs, long ncRNAs and circular RNAs, are deregulated in many orthopaedic diseases, including scoliosis. Importantly, these deregulated ncRNAs functionally participate in the initiation and progression of scoliosis. Here, we review recent progress in ncRNA research on scoliosis.     

Musculoskeletal deformities following treatment of Wilms' tumour.

Wilms'' tumour is one of the most common neoplasms of infancy and childhood. Current treatment regimens result in a cure rate of about 80% for localized tumours but may also cause musculoskeletal deformities. Assessment of 21 patients previously treated for Wilms'' tumour showed that all had flank atrophy on the treated side. Radiologic abnormalities included asymmetry of vertebral bodies, vertebral end-plate irregularities, scoliosis, kyphosis, platyspondyly and hypoplasia of the ilium. Although the vertebral changes following radiotherapy for Wilms'' tumour are present from an early age and the potential is great for an increase in spinal deformity with growth, few spinal curves progress past 20 degree. Since one cannot predict which curves will progress, all such patients need careful orthopedic follow-up until skeletal maturity is achieved.     

Scoliosis in the community.

Screening for scoliosis at schools has become more and more popular despite the lack of knowledge concerning the clinical course of idiopathic scoliosis. An epidemiological study of 5303 schoolchildren showed three types of scoliosis in the community: (1) pelvic tilt scoliosis (an inconsequential deformity caused by an inequality in the length of the legs but accounting for almost 40% of curves detected); (2) spinal scoliosis (a minor asymmetry of the spine in the coronal plane that tends to remain static or to resolve and which may be normal in growing children, accounting for the remaining 60%); and (3) progressive scoliosis (10% of the spinal scolioses measuring 10 degrees or more that progress by 5 degrees or more a year). Progressive scoliosis resembles idiopathic scoliosis because in girls with right thoracic curves the potential for progression is appreciable. Until the natural history is better established growing awareness in the community of spinal deformity should help earlier detection, and screening should be directed towards providing subjects for further epidemiological work.     

Vertebral defects in fourhorn sculpin, Myoxocephalus quadricornis L., exposed to heavy metal pollution in the Gulf of Bothnia

Vertebral defects in adult fourhorn sculpin were used to trace heavy metal pollution in the Gulf of Bothnia (Baltic Sea). From 1978 to 1984 a total of 9789 specimens from 22 localities were X-rayed and analysed for vertebral deformities, e.g., scoliosis, deformation and/or dislocation of individual vertebrae, etc. The frequency of fish with vertebral defects ranged between 4.3 and 39.7%, the highest frequencies being found in the vicinity of a metal ore smeltery (Rönnskärsverken) emitting heavy metals and arsenic. The possible influence of genetic factors, migration, sex, size, age and parasitic infections on the results are discussed and evaluated.     

The three-dimensional easy morphological (3-DEMO) classification of scoliosis – Part III, correlation with clinical classification and parameters

Background

The shape of the torso in patients with idiopathic scoliosis is considered to reflect the shape of the vertebral column, however the direct correlation between parameters describing clinical deformity and those characterizing radiological curvature was reported to be weak. It is not clear if the management proposed for scoliosis (physiotherapy, brace, surgery) affects equally the shape of the axial skeleton and the surface of the body. The aim of the study was to compare clinical deformity of (1) idiopathic scoliosis girls being under brace treatment for radiological curves of 25 to 40 degrees and (2) non treated scoliotic girls matched for age and Cobb angle.

Methods

Cross-sectional study of 24 girls wearing the brace versus 26 girls without brace treatment, matched for age and Cobb angle. Hypothesis: Patients wearing the brace for more than 6 months, when comparing to patients without brace, may present different external morphology of the trunk, in spite of having similar Cobb angle. Material. Inclusion criteria: girls, idiopathic scoliosis, growing age (10–16 years), Cobb angle minimum 25°, maximum 40°. The braced group consisted of girls wearing a TLSO brace (Cheneau) for more than 6 months with minimum of 16 hours per day. The non-braced group consisted of girls first seen for their spinal deformity, previously not treated. The groups presented similar curve pattern. Methods. Scoliometer exam: angle of trunk rotation at three levels of the spine: upper thoracic, main thoracic, lumbar or thoracolumbar. The maximal angle was noted at each level and the sum of three levels was calculated. Posterior trunk symmetry index (POTSI) and Hump Sum were measured using surface topography.

Results

Cobb angle was 34.9° ± 4.8° in braced and 32.7° ± 4.9° in un-braced patients (difference not significant). The age was 14.1 ± 1.6 years in braced patients and 13.1 ± 1.9 years in un-braced group (p = 0.046). The value of angle of trunk rotation in the main curvature was 8.4° ± 2.7°in braced and 11.4° ± 2.7° in un-braced patients (difference extremely significant, p = 0.0003). The value of the sum of angles of trunk rotation at three levels of the trunk was 12.8° ± 4.6° in braced and 16.5° ± 3.8° in un-braced patients (difference very significant, p = 0.0038). The POTSI did not differ significantly between the groups (p = 0.78), the Hump Sum values were not quite different (p = 0.07).

Conclusion

(1) Adolescent girls wearing the brace for idiopathic scoliosis of 25 to 40 degrees of Cobb angle, reveal smaller clinical rotational deformity of their back than non-treated girls having similar radiological deformity. (2) evaluation of the results of treatment for idiopathic scoliosis should consider parameters describing both clinical and radiological deformity.     

Three-Dimensional Vertebral Wedging in Mild and Moderate Adolescent Idiopathic Scoliosis

Background

Vertebral wedging is associated with spinal deformity progression in adolescent idiopathic scoliosis. Reporting frontal and sagittal wedging separately could be misleading since these are projected values of a single three-dimensional deformation of the vertebral body. The objectives of this study were to determine if three-dimensional vertebral body wedging is present in mild scoliosis and if there are a preferential vertebral level, position and plane of deformation with increasing scoliotic severity.

Methodology

Twenty-seven adolescent idiopathic scoliotic girls with mild to moderate Cobb angles (10° to 50°) participated in this study. All subjects had at least one set of bi-planar radiographs taken with the EOS® X-ray imaging system prior to any treatment. Subjects were divided into two groups, separating the mild (under 20°) from the moderate (20° and over) spinal scoliotic deformities. Wedging was calculated in three different geometric planes with respect to the smallest edge of the vertebral body.

Results

Factorial analyses of variance revealed a main effect for the scoliosis severity but no main effect of vertebral Levels (apex and each of the three vertebrae above and below it) (F = 1.78, p = 0.101). Main effects of vertebral Positions (apex and above or below it) (F = 4.20, p = 0.015) and wedging Planes (F = 34.36, p<0.001) were also noted. Post-hoc analysis demonstrated a greater wedging in the inferior group of vertebrae (3.6°) than the superior group (2.9°, p = 0.019) and a significantly greater wedging (p≤0.03) along the sagittal plane (4.3°).

Conclusions

Vertebral wedging was present in mild scoliosis and increased as the scoliosis progressed. The greater wedging of the inferior group of vertebrae could be important in estimating the most distal vertebral segment to be restrained by bracing or to be fused in surgery. Largest vertebral body wedging values obtained in the sagittal plane support the claim that scoliosis could be initiated through a hypokyphosis.     

Using Skin Markers for Spinal Curvature Quantification in Main Thoracic Adolescent Idiopathic Scoliosis: An Explorative Radiographic Study

Background and Purpose

Although the relevance of understanding spinal kinematics during functional activities in patients with complex spinal deformities is undisputed among researchers and clinicians, evidence using skin marker-based motion capture systems is still limited to a handful of studies, mostly conducted on healthy subjects and using non-validated marker configurations. The current study therefore aimed to explore the validity of a previously developed enhanced trunk marker set for the static measurement of spinal curvature angles in patients with main thoracic adolescent idiopathic scoliosis. In addition, the impact of inaccurate marker placement on curvature angle calculation was investigated.

Methods

Ten patients (Cobb angle: 44.4±17.7 degrees) were equipped with radio-opaque markers on selected spinous processes and underwent a standard biplanar radiographic examination. Subsequently, radio-opaque markers were replaced with retro-reflective markers and the patients were measured statically using a Vicon motion capture system. Thoracolumbar / lumbar and thoracic curvature angles in the sagittal and frontal planes were calculated based on the centers of area of the vertebral bodies and radio-opaque markers as well as the three-dimensional position of the retro-reflective markers. To investigate curvature angle estimation accuracy, linear regression analyses among the respective parameters were used. The impact of inaccurate marker placement was explored using linear regression analyses among the radio-opaque marker- and spinous process-derived curvature angles.

Results and Discussion

The results demonstrate that curvatures angles in the sagittal plane can be measured with reasonable accuracy, whereas in the frontal plane, angles were systematically underestimated, mainly due to the positional and structural deformities of the scoliotic vertebrae. Inaccuracy of marker placement had a greater impact on thoracolumbar / lumbar than thoracic curvature angles. It is suggested that spinal curvature measurements are included in marker-based clinical gait analysis protocols in order to enable a deeper understanding of the biomechanical behavior of the healthy and pathological spine in dynamic situations as well as to comprehensively evaluate treatment effects.     

A mechanism for gene-environment interaction in the etiology of congenital scoliosis

Congenital scoliosis, a lateral curvature of the spine caused by vertebral defects, occurs in approximately 1 in 1,000 live births. Here we demonstrate that haploinsufficiency of Notch signaling pathway genes in humans can cause this congenital abnormality. We also show that in a mouse model, the combination of this genetic risk factor with an environmental condition (short-term gestational hypoxia) significantly increases the penetrance and severity of vertebral defects. We demonstrate that hypoxia disrupts FGF signaling, leading to a temporary failure of embryonic somitogenesis. Our results potentially provide a mechanism for the genesis of a host of common sporadic congenital abnormalities through gene-environment interaction.     

Adolescent idiopathic scoliosis as developmental instability

Adolescent idiopathic scoliosis is the most common spinal deformity affecting children, with a prevalence from mass screening programmes of 1–3%. Despite centuries of study, it remains a problem with no generally accepted theory of aetiology, and disagreement on its natural history and management. Because the deformity consists ultimately of gross left-right asymmetry, a study was undertaken to test the hypothesis that it might be a manifestation of developmental instability. Palmar dermatoglyphics in 112 normal subjects, 62 with non-scoliosis trunk asymmetry and 85 with defined adolescent idiopathic scoliosis were examined and both the absolute right-left difference and the ratio of this to the total were considered. There was increased fluctuating asymmetry of atd difference in those with any asymmetry, scoliotic or not, and increased directional asymmetry of ab and cd ridge counts only in those with pure scoliosis. This suggests that, at adolescence, developmental instability may result in a loss of symmetry in growth, and that in the presence of an increased developmental left-right gradient, this may be of sufficient severity to be classified as deformity and come to the attention of orthopaedic surgeons. This interpretation changes the focus of many previous observations on scoliosis and raises the prospect that developmental stability in humans has relevance to problems hitherto restricted to clinical practice.     

Dystrophic Spinal Deformities in a Neurofibromatosis Type 1 Murine Model

Despite the high prevalence and significant morbidity of spinal anomalies in neurofibromatosis type 1 (NF1), the pathogenesis of these defects remains largely unknown. Here, we present two murine models: Nf1^flox/−;PeriCre and Nf1^flox/−;Col.2.3Cre mice, which recapitulate spinal deformities seen in the human disease. Dynamic histomorphometry and microtomographic studies show recalcitrant bone remodeling and distorted bone microarchitecture within the vertebral spine of Nf1^flox/−;PeriCre and Nf1^flox/−;Col2.3Cre mice, with analogous histological features present in a human patient with dystrophic scoliosis. Intriguingly, 36–60% of Nf1^flox/−;PeriCre and Nf1^flox/−;Col2.3Cre mice exhibit segmental vertebral fusion anomalies with boney obliteration of the intervertebral disc (IVD). While analogous findings have not yet been reported in the NF1 patient population, we herein present two case reports of IVD defects and interarticular vertebral fusion in patients with NF1. Collectively, these data provide novel insights regarding the pathophysiology of dystrophic spinal anomalies in NF1, and provide impetus for future radiographic analyses of larger patient cohorts to determine whether IVD and vertebral fusion defects may have been previously overlooked or underreported in the NF1 patient population.     

Three-dimensional osseo-ligamentous model of the thorax representing initiation of scoliosis by asymmetric growth

A biomechanical model of the human thorax was constructed to investigate how asymmetric growth of the thorax might initiate spinal lateral curvature and axial rotation as seen in scoliosis deformities. Geometric data specifying nodal points of the model were taken from stereo-radiographs of an adolescent subject. An initially symmetrical geometry was created by 'mirroring' measurements of a hemi-thorax and spine. Published data provided cross-sectional measurements of the ribs, material properties of tissues and global flexibilities of the intervertebral motion segments. The ribs, sternum, intervertebral motion segments and intercostal ligaments were represented by elastic elements. Model deformations were calculated by the direct stiffness finite element method, with growth represented by an initial strain term in the constitutive law. Non-linear behavior was accommodated by running the model recursively, with updated node locations at each step. Both stress relaxation and stress modulation of growth in the component tissues were simulated. Thoracic growth of 20% with asymmetric growth of the ribs was simulated to give rib length asymmetries of 11%. similar to that observed in a previous study of patients with idiopathic scoliosis. This resulted in the model having a small thoracic scoliosis curvature convex toward the side of the longer ribs. Variations of the model which permitted free motion at the costo-vertebral joints or produced changes in the curvature of the posterior parts of the ribs resulted in axial rotation of the vertebrae similar to that observed clinically. The model supports the idea that growth asymmetry could initiate a small scoliosis during adolescence.