Transforming growth factor-beta (TGF- ?) signaling in paravertebral muscles in juvenile and adolescent idiopathic scoliosis.
ABSTRACT: Most researchers agree that idiopathic scoliosis (IS) is a multifactorial disease influenced by complex genetic and environmental factors. The onset of the spinal deformity that determines the natural course of the disease, usually occurs in the juvenile or adolescent period. Transforming growth factors ? (TGF-?s) and their receptors, TGFBRs, may be considered as candidate genes related to IS susceptibility and natural history. This study explores the transcriptional profile of TGF-?s, TGFBRs, and TGF-? responsive genes in the paravertebral muscles of patients with juvenile and adolescent idiopathic scoliosis (JIS and AIS, resp.). Muscle specimens were harvested intraoperatively and grouped according to the side of the curve and the age of scoliosis onset. The results of microarray and qRT-PCR analysis confirmed significantly higher transcript abundances of TGF-?2, TGF-?3, and TGFBR2 in samples from the curve concavity of AIS patients, suggesting a difference in TGF-? signaling in the pathogenesis of juvenile and adolescent curves. Analysis of TGF-? responsive genes in the transcriptomes of patients with AIS suggested overrepresentation of the genes localized in the extracellular region of curve concavity: LTBP3, LTBP4, ITGB4, and ITGB5. This finding suggests the extracellular region of paravertebral muscles as an interesting target for future molecular research into AIS pathogenesis.
Project description:The purpose of the study was to determine differences in mRNA concentration of VDR isoforms in bone, cartilage and paravertebral muscles between tissues from curve concavity and convexity, between JIS and AIS and to identify VDR responsive genes differentiating Juvenile and Adolescent Idiopathic Scoliosis in paravertebral muscles.
Project description:Adolescent idiopathic scoliosis (AIS) is the most common paediatric spinal deformity. The etiology and pathology of AIS remain unexplained, and have been reported to involve a combination of genetic and epigenetic factors. Since paravertebral muscle imbalance plays an important role in the onset and progression of scoliosis, we aimed to investigate transcriptomic differences by RNA-seq and identify significantly differentially expressed transcripts in two sides of paravertebral muscle in AIS.RNA-seq was performed on 5 pairs of paravertebral muscle from 5 AIS patients. Significantly differentially expressed transcripts were validated by quantitative reverse polymerase chain reaction. Gene expression difference was correlated to clinical characteristics.We demonstrated that ADIPOQ mRNA and H19 is significantly differentially expressed between two sides of paravertebral muscle, relatively specific in the context of AIS. Relatively low H19 and high ADIPOQ mRNA expression levels in concave-sided muscle are associated with larger spinal curve and earlier age at initiation. We identified miR-675-5p encoded by H19 as a mechanistic regulator of ADIPOQ expression in AIS. We demonstrated that significantly reduced CCCTC-binding factor (CCTF) occupancy in the imprinting control region (ICR) of the H19 gene in the concave-sided muscle contributes to down-regulated H19 expression.RNA-seq revealed transcriptomic differences between two sides of paravertebral muscle in AIS patients. Our findings imply that transcriptomic differences caused by epigenetic factors in affected individuals may account for the structural and functional imbalance of paravertebral muscle, which can expand our etiologic understanding of this disease.
Project description:Muscle imbalance has been suggested as implicated in the pathology of adolescent idiopathic scoliosis (AIS). The specific "pathomechanic" role of the paravertebral muscles as being scoliogenic (inducing scoliosis) or counteracting scoliosis in the initial development and maintenance of this spinal deformity has yet to be clarified in humans. In the present study, we investigated the radiographic changes of temporal paralysis using botulinum toxin A as localized injection therapy (ITB) in the psoas major muscle in AIS patients.Nine patients with AIS were injected one time with ITB using ultrasonic and EMG guidance in the selected spine muscles. Radiographic and clinical examinations were performed before and 6 weeks after the injection. Primary outcome parameters of radiological changes were analyzed using Wilcoxon signed-rank test and binomial test, and secondary outcome parameters of short- and long-term clinical effects were obtained.Significant radiological corrective changes were seen in the frontal plane in the thoracic and lumbar spine as well as significant derotational corrective change in the lumbar spine according to Cobb's angle measurements and to Nash and Moe's classification, respectively. No serious adverse events were detected at follow-up.In conclusion, this study demonstrated that the psoas major muscle do play a role into the pathology in adolescent idiopathic scoliosis by maintaining the curvature of the lumbar spine and thoracic spine.EudraCT number 2008-004584-19.
Project description:Over the last years, evidence has accumulated in support of bracing as an effective treatment option in patients with idiopathic scoliosis. Yet, little information is available on the impact of compliance on the outcome of conservative treatment in scoliotic subjects. The aim of the present study was to prospectively evaluate the association between compliance to brace treatment and the progression of scoliotic curve in patients with idiopathic adolescent (AIS) or juvenile scoliosis (JIS).Among 1.424 patients treated for idiopathic scoliosis, 645 were eligible for inclusion criteria. Three outcomes were distinguished in agreement with the SRS criteria: curve correction, curve stabilization and curve progression. Brace wearing was assessed by one orthopaedic surgeon (LA) and scored on a standardized form. Compliance to treatment was categorized as complete (brace worn as prescribed), incomplete A (brace removed for 1 month), incomplete B (brace removed for 2 months), incomplete C (brace removed during school hours), and incomplete D (brace worn overnight only). Chi square test, T test or ANOVA and ANOVA for repeated measures tests were used as statistical tests.The results from our study showed that at follow-up the compliance was: Complete 61.1%; Incomplete A 5.2%; Incomplete B 10.7%; Incomplete C 14.2%; Incomplete D 8.8%. Curve correction was accomplished in 301/319 of Complete, 19/27 Incomplete A, 25/56 Incomplete B, 52/74 Incomplete C, 27/46 Incomplete D. Cobb mean value was 29.8?±?7.5 SD at beginning and 17.1?±?10.9 SD at follow-up. Both Cobb and Perdriolle degree amelioration was significantly higher in patients with complete compliance over all other groups, both in juvenile, both in adolescent scoliosis. In the intention-to-treat analysis, the rate of surgical treatment was 2.1% among patients with definite outcome and 12.1% among those with drop-out. Treatment compliance showed significant interactions with time.Curve progression and referral to surgery are lower in patients with high brace compliance. Bracing discontinuation up to 1 month does not impact on the treatment outcome. Conversely, wearing the brace only overnight is associated with a high rate of curve progression.
Project description:It is recommended that research in patients with idiopathic scoliosis should focus on short- and long-term patient-centred outcome. The aim of the present study was to evaluate outcome in patients with late-onset juvenile or adolescent idiopathic scoliosis 16 years or more after Boston brace treatment.272 (78%) of 360 patients, 251 (92%) women, responded to follow-up examination at a mean of 24.7 (range 16 - 32) years after Boston brace treatment. Fifty-eight (21%) patients had late-onset juvenile and 214 had adolescent idiopathic scoliosis. All patients had clinical and radiological examination and answered a standardised questionnaire including work status, demographics, General Function Score (GFS) (100 - worst possible) and Oswestry Disability Index (ODI) (100 - worst possible), EuroQol (EQ-5D) (1 - best possible), EQ-VAS (100 - best possible), and Scoliosis Research Society - 22 (SRS - 22) (5 - best possible).The mean age at follow-up was 40.4 (31-48) years. The prebrace major curve was in average 33.2 (20 - 57)°. At weaning and at the last follow-up the corresponding values were 28.3 (1 - 58)° and 32.5 (7 - 80)°, respectively. Curve development was similar in patients with late-onset juvenile and adolescent start. The prebrace curve increased > 5° in 31% and decreased > 5° in 26%. Twenty-five patients had surgery. Those who did not attend follow-up (n = 88) had a lower mean curve at weaning: 25.4 (6-53)°. Work status was 76% full-time and 10% part-time. Eighty-seven percent had delivered a baby, 50% had pain in pregnancy. The mean (SD) GFS was 7.4 (10.8), ODI 9.3 (11.0), EQ-5D 0.82 (0.2), EQ-VAS 77.6 (17.8), SRS-22: pain 4.1 (0.8), mental health 4.1 (0.6), self-image 3.7 (0.7), function 4.0 (0.6), satisfaction with treatment 3.7 (1.0). Surgical patients had significantly reduced scores for SRS-physical function and self-image, and patients with curves ? 45° had reduced self-image.Long-term results were satisfactory in most braced patients and similar in late-onset juvenile and idiopathic adolescent scoliosis.
Project description:Scoliosis is a complex three-dimensional spine deformity with the frontal plane deflexion (side-shift) of the series of vertebra from the midline and with torque deformity of vertebra, ribs, and the entire trunk towards the apex of curve. Chronic venous diseases present a group of pathological conditions caused by the increased venous pressure. The venous pressure may be increased due to genetics, ligament laxity, general obesity, injuries, and changes in biomechanics of spine and lower extremities, etc.The aim of the study is to evaluate the frequency of the varicose veins in women previously treated for the adolescent idiopathic scoliosis.In the period August 1, 2015 - December 30, 2015 the Team for scoliosis in the Institute for the Physical medicine and Rehabilitation "Dr Miroslav Zotović" in Banja Luka in study program has clinically assessed 89 women previously treated for the adolescent idiopathic scoliosis (AIS) and the control group of 87 women without history of scoliosis.Results of the study led to conclusion that occurrence of the varicose veins was more frequent in the group of women who were treated for the AIS (23/89 or 25.8%) in comparison with control group with no history of AIS (7/87 or 8.1%).This might relate AIS with some other connective tissue disorder, like venous varices, for instance.
Project description:Adolescent idiopathic scoliosis (AIS) is the peripubertal development of spinal curvature of a minimum of 10°. AIS is thought to be attributable to genetic factors, nutrition, early exposure to toxins, and hormonal dysregulation. Recent literature suggests these factors may compound to determine both disease onset and severity. Currently, treatment is limited to observation, bracing, and surgical intervention. Intervention is presently determined by severity and risk of curve progression. As they emerge, new therapies may target specific etiologies of AIS.
Project description:Adolescent idiopathic scoliosis (AIS) is the most common spinal deformity in children. Studies have shown low melatonin levels resulting from pinealectomy in chickens and mice result in the development scoliosis, whereas supplementation with melatonin after the pinealectomy prevented it. The mere characterization of low melatonin levels is not sufficient to explain the development of idiopathic scoliosis in primates and humans, but we hypothesize that a mutation in melatonin-related receptors may be involved with the development of scoliosis.The coding, splice-site, and promoter regions of 3 melatonin-related receptors (hMel-1B, RORalpha, and GPR50) were evaluated by DNA sequencing for variants associated with the phenotype of adolescent idiopathic scoliosis. An initial screening of 50 scoliosis patients with adolescent idiopathic scoliosis was compared with 50 controls by DNA sequencing of the 3 receptors. Additional cases and controls were evaluated when genetic variants were observed (for a total of 885 individuals).No significant differences were found in the hMel-1B and RORalpha receptors. We found 2 cSNPs in GPR50 (rs561077 and rs13440581) in the initial 50 patients. To evaluate the significance of these cSNPs, an additional 356 patients and 429 controls were analyzed. When the combined groups were analyzed, no significant associations were observed.Despite the observed relationship between melatonin and scoliosis, there is no significant association between mutations found in any known melatonin-related receptors with adolescent idiopathic scoliosis. The strong evidence of a melatonin-related cause for the development of idiopathic scoliosis still encourages research into undiscovered melatonin-related receptors, melatonin-related hormones, and the catalytic enzymes for the serotonin-melatonin pathway.This investigation is a genetic testing of the remaining currently known melatonin-related receptors that have not been analyzed earlier for association with AIS. Given the support in the literature of a relationship between melatonin and AIS, we have shown no mutations in any of the known melatonin-related receptor in patients with AIS.
Project description:(1) Background: Adolescent idiopathic scoliosis (AIS) can be associated with vitamin D deficiency and osteopenia. Plantar pressure and stabilometry offer important information about posture. The objectives of our study were to compare static plantar pressure and stabilometric parameters, serum 25-OH-vitamin D3 and calcium levels, and bone mineral densitometry expressed as z-score in patients with moderate AIS and healthy subjects. (2) Methods: 32 female adolescents (idiopathic S shaped moderate scoliosis, main lumbar curve) and 32 gender and age-matched controls performed: static plantar pressure, stabilometry, serum 25-OH-vitamin D3 and calcium levels, and dual X-ray absorptiometry scans of the spine. (3) Results: In scoliosis patients, significant differences were recorded between right and left foot for total foot, first and fifth metatarsal, and heel loadings. Stabilometry showed a poorer postural control when compared to healthy subjects (p < 0.001). Patients had significantly lower vitamin D, calcium levels, and z-scores. Lumbar Cobb angle was significantly correlated with the z-score (r = -0.39, p = 0.02), with right foot fifth metatarsal load (r = -0.35, p = 0.04), center of pressure CoPx (r = -0.42, p = 0.01), CoP displacement (r = 0.35, p = 0.04) and 90% confidence ellipse area (r = -0.38, p = 0.03). (4) Conclusions: In our study including female adolescents with idiopathic S shaped moderate scoliosis, plantar pressure and stabilometric parameters were influenced by the main scoliotic curve.
Project description:OBJECTIVE: Idiopathic scoliosis is the most common pediatric spinal deformity affecting 1% to 3% of the population, and adolescent idiopathic scoliosis (AIS) accounts for approximately 80% of these cases; however, the etiology and pathogenesis of AIS are still uncertain. The current study aims to identify the relationship between calmodulin 1 (CALM1) gene and AIS predisposition, to identify the relationship between the genotypes of the SNPs and the clinical phenotypes of AIS. METHODS: 146 AIS patients and 146 healthy controls were enrolled into this case-control study. 12 single nucleotide polymorphisms (SNPs) candidates in CALM1 gene were selected to determine the relationship between CALM1 gene and AIS predisposition. Case-only study was performed to determine the effects of these variants on the severity of the condition. RESULTS: Three SNPs from 12 candidates were found to be associated with AIS predisposition. The ORs were observed as 0.549 (95% CI 0.3519-0.8579, P = 0.0079), 0.549 (95% CI 0.3519-0.8579, P = 0.0079), and 1.6139 (95% CI 1.0576-2.4634, P = 0.0257) for rs2300496, rs2300500, and rs3231718, respectively. There was no statistical difference between main curve, severity, and genotype distributions of all of 12 SNPs. CONCLUSION: Genetic variants of CALM1 gene are associated with AIS susceptibility.