Neuroinflammatory signals drive spinal curve formation in zebrafish models of idiopathic scoliosis.
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ABSTRACT:
SUBMITTER: Van Gennip JLM
PROVIDER: S-EPMC6291318 | biostudies-literature | 2018 Dec
REPOSITORIES: biostudies-literature
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Project description:Idiopathic scoliosis (IS) affects 3% of children worldwide, yet the mechanisms underlying this spinal deformity remain unknown. Here we show that ptk7 mutant zebrafish, a faithful developmental model of IS, exhibit defects in ependymal cell cilia development and cerebrospinal fluid (CSF) flow. Transgenic reintroduction of Ptk7 in motile ciliated lineages prevents scoliosis in ptk7 mutants, and mutation of multiple independent cilia motility genes yields IS phenotypes. We define a finite developmental window for motile cilia in zebrafish spine morphogenesis. Notably, restoration of cilia motility after the onset of scoliosis blocks spinal curve progression. Together, our results indicate a critical role for cilia-driven CSF flow in spine development, implicate irregularities in CSF flow as an underlying biological cause of IS, and suggest that noninvasive therapeutic intervention may prevent severe scoliosis.
| S-EPMC5574193 | biostudies-literature
Project description:Adolescent idiopathic scoliosis (AIS) is a three-dimensional (3D) deformity of the spinal column. For progressive deformities in AIS, the spinal fusion surgery aims to correct and stabilize the deformity; however, common surgical planning approaches based on the 2D X-rays and subjective surgical decision-making have been challenged by poor clinical outcomes. As the suboptimal surgical outcomes can significantly impact the cost, risk of revision surgery, and long-term rehabilitation of adolescent patients, objective patient-specific models that predict the outcome of different treatment scenarios are in high demand. 3D classification of the spinal curvature and identifying the key surgical parameters influencing the outcomes are required for such models. Here, we show that K-means clustering of the isotropically scaled 3D spinal curves provides an effective, data-driven method for classification of patients. We further propose, and evaluate in 67 right thoracic AIS patients, that by knowing the patients' pre-operative and early post-operation clusters and the vertebral levels which were instrumented during the surgery, the two-year outcome cluster can be determined. This framework, once applied to a larger heterogeneous patient dataset, can further isolate the key surgeon-modifiable parameters and eventually lead to a patient-specific predictive model based on a limited number of factors determinable prior to surgery.
| S-EPMC6214965 | biostudies-literature
Project description:One of the first morphogenetic events in the vertebrate brain is the formation of the highly conserved midbrain-hindbrain boundary (MHB). Specific cell shape changes occur at the point of deepest constriction of the MHB, the midbrain-hindbrain boundary constriction (MHBC), and are critical for proper MHB formation. These cell shape changes are controlled by nonmuscle myosin II (NMII) motor proteins, which are tightly regulated via the phosphorylation of their associated myosin regulatory light chains (MRLCs). However, the upstream signaling pathways that initiate the regulation of NMII to mediate cell shape changes during MHB morphogenesis are not known. We show that intracellular calcium signals are critical for the regulation of cell shortening during initial MHB formation. We demonstrate that the MHB region is poised to respond to calcium transients that occur in the MHB at the onset of MHB morphogenesis and that calcium mediates phosphorylation of MRLC specifically in MHB tissue. Our results indicate that calmodulin 1a (calm1a), expressed specifically in the MHB, and myosin light chain kinase together mediate MHBC cell length. Our data suggest that modulation of NMII activity by calcium is critical for proper regulation of cell length to determine embryonic brain shape during development.
| S-EPMC5385936 | biostudies-literature
Project description:Scoliosis is a complex genetic disorder of the musculoskeletal system, characterized by three-dimensional rotation of the spine. Curvatures caused by malformed vertebrae (congenital scoliosis (CS)) are apparent at birth. Spinal curvatures with no underlying vertebral abnormality (idiopathic scoliosis (IS)) most commonly manifest during adolescence. The genetic and biological mechanisms responsible for IS remain poorly understood due largely to limited experimental models. Here we describe zygotic ptk7 (Zptk7) mutant zebrafish, deficient in a critical regulator of Wnt signalling, as the first genetically defined developmental model of IS. We identify a novel sequence variant within a single IS patient that disrupts PTK7 function, consistent with a role for dysregulated Wnt activity in disease pathogenesis. Furthermore, we demonstrate that embryonic loss-of-gene function in maternal-zygotic ptk7 mutants (MZptk7) leads to vertebral anomalies associated with CS. Our data suggest novel molecular origins of, and genetic links between, congenital and idiopathic forms of disease.
| S-EPMC4155517 | biostudies-literature
Project description:BackgroundAdolescent idiopathic scoliosis (AIS) is common deformity with unknown cause. Previous studies have suggested the abnormal serum leptin and ghrelin level in AIS girls. The aim of present study was to evaluate whether the serum leptin and ghrelin level could serve as risk factor in predicting the curve progression in AIS girls. The associations between them and the physical characteristics were also investigated.Materials and methodsCirculating leptin and ghrelin levels from 105 AIS girls and 40 age-matched non-AIS girls were examined by enzyme-linked immunosorbent assay. The correlations between ghrelin and leptin levels and growth-related parameters (age, weight, corrected height, corrected BMI, main Cobb angle, and Risser sign) were analyzed in AIS group. Multivariate logistic regression was used to investigate factors predicting curve progression in AIS girls.ResultsA significantly lower leptin level (6.55 ± 2.88 vs. 8.01 ± 3.12?ng/ml, p < 0.05) and a higher ghrelin level (6.33 ± 2.46 vs. 4.46 ± 2.02?ng/ml, p < 0.05) were found in all AIS patients, as compared with normal controls. Curve progression patients had a higher ghrelin level than stable curve patients (7.61 ± 2.48 vs. 5.54 ± 2.11?ng/ml, p < 0.01); for leptin level, there was no significant difference between progression and stable group. The results of multivariate logistic stepwise regression showed that premenarche status, initial main Cobb magnitude that was more than or equal to 23°, high ghrelin level (?7.30?ng/ml), and lower Risser grade (grades 0 to 2) were identified as risk factors in predicting curve progression. Ghrelin levels of >6.48?ng/ml were predictive for curve progression with 70.00 % sensitivity and 72.31 % specificity, and the area under the curve (AUC) was 0.741 (95 % confidence interval 0.646-0.821).ConclusionsHigh ghrelin level may serve as a new quantitative indicator for predicting curve progression in AIS girls.
| S-EPMC6069699 | biostudies-literature
Project description:BackgroundThere is an acknowledged discrepancy between radiographic and cosmetic parameters for patients with adolescent idiopathic scoliosis (AIS). However, no study has specifically evaluated cosmesis in patients with congenital scoliosis (CS). Therefore, the purpose of this study was to identify the cosmetic differences between patients with CS and case-matched patients with AIS and to investigate the correlation between radiological measurements and clinical cosmetic assessment indices.MethodsA total of 37 adolescents with CS and 37 sex-, age-, and curve magnitude-matched patients with AIS were included. Cobb angle, shoulder height difference (SHD), coronal balance (CB), T1 tilt, first rib angle (FRA), clavicle angle (CA), clavicle-rib cage intersection (CRCI), and apical vertebra translation (AVT) were measured in the full X-ray of the spine. Shoulder area index 1 (SAI1), shoulder area index 2 (SAI2), shoulder angle (SA), axilla angle (AA), thoracolumbar area index (TLAI), and right and left waist angle difference (RLWAD) were measured on the clinical images from a posterior view. Hump index (HI) was measured in the forward bending photography. All patients completed the Scoliosis Research Society-22 (SRS-22) questionnaire.ResultsNo significant difference was noted in the radiographic parameters between the AIS and CS groups (P>0.05). However, patients with CS exhibited significantly lower SAI1 (0.91 vs. 0.98; P=0.002) and SAI2 (0.85 vs. 0.95; P=0.001) than did the patients with AIS. The SRS-22 scores for self-image and mental health in patients with CS were significantly lower than those in patients with AIS (P<0.05). The correlation coefficients with statistical significance between radiographic and cosmetic measurements in patients with CS and those with AIS ranged from -0.493 to 0.534 and from -0.653 to 0.717, respectively. None of the correlation coefficients exceeded 0.8, indicating that the current radiological indices only exhibited a limited level of consistency with patients' cosmesis.ConclusionsAs compared with age-, gender-, and curve pattern-matched patients with AIS, patients with CS exhibited worse cosmesis and had clinically significantly lower SRS-22 scores despite having relatively small clinical differences. Although the radiographic parameters may not always align with clinical presentation, this discrepancy could be observed in both patients with CS and those with AIS.
| S-EPMC10498239 | biostudies-literature
Project description:There is no consensus on the definition of a structural proximal thoracic curve (PTC) and the indications for fusion. As such, we assessed a single institute's experience in the management of large PTCs (>35 degrees) in patients with adolescent idiopathic scoliosis (AIS) who were either fused or not fused. A retrospective radiographic analyses of 30 consecutive AIS patients with double thoracic curves who underwent PSF with a minimum of 2 years' follow-up were included for review. The patients were divided into two groups: group 1 (n = 15 patients) with fusion extended up to T2 or T3 and group 2 (n = 15) with fusion limited to T5 or below. Shoulder balance was assessed according to clavicular angle, first-rib difference, and radiographic shoulder height difference (SHD). PTCs were defined based on a Cobb angle of >35, the presence of apical rotation, and a positive T1 tilt. The decision to fuse the PTC was based on curve magnitude only, with those between 35 and 45 degrees undergoing a selective fusion of the main thoracic curve (MTC), with both curves fused if the PTC was more than 45 degrees. In group 1, there were eight females and seven males. Their ages ranged between 12 and 33 years, with a mean of 16.2 ± 5.5 years. Postoperatively, the mean PTC correction was 45.6%, which statistically differed from preoperative status (p = 0.001). No statistical difference was noted in T1 tilt and the first-rib difference from preoperative to postoperative follow-up (p > 0.05). However, the clavicular angle and SHD were increased significantly at the immediate postoperative interval (p < 0.05) but demonstrated no significant changes between the initial and the last follow-up values (p > 0.05). Group 2 consisted of one male and 14 females. The mean age was 16.4 ± 4 years (range: 11 to 28 years). The mean spontaneous PTC correction was 28.3% and remained essentially unchanged at the end of the follow-up. The improvement in the curve from preoperative status was highly statistically significant (p = 0.001). All radiographic shoulder parameters exhibited a significant increase in the immediate postoperative period and at last follow-up, and shoulder balance improvement was not noted on follow-up. Although both groups were not statistically similar with regards to the preoperative PTC, AVR, apical vertebral translation, and shoulder parameters, no significant difference could be found in PTC or shoulder parameters between both groups at last follow-up (p > 0.05). Our study illustrates important observations that should be considered in defining the PTC for fusion consideration. Spontaneous correction of the PTC occurs in structural curves greater than 35 degrees and less than 45 degrees, and this correction is maintained over time. Despite that correction, radiographic shoulder parameters are expected to slightly increase. Nonfusion strategy may be appropriate for PTCs between 35 and 45 degrees. After fusion of both the MTC and the PTC, the radiographic shoulder parameters did not significantly differ. Preoperative radiographic shoulder parameters are not predictive of postoperative shoulder imbalance.
| S-EPMC3864415 | biostudies-other
Project description:Background:In adolescent idiopathic scoliosis (AIS), the continuous search for effective prognostication of significant curve progression at the initial clinical consultation to inform decision for timely treatment and to avoid unnecessary overtreatment remains a big challenge as evidence of the multifactorial etiopathogenic nature is increasingly reported. This study aimed to formulate a composite model composed of clinical parameters and circulating markers in the prediction of curve progression. Method:This is a two-phase study consisting of an exploration cohort (120 AIS, mean Cobb angle of 25°± 8.5 at their first clinical visit) and a validation cohort (51 AIS, mean Cobb angle of 23° ± 5.0° at the first visit). Patients with AIS were followed-up for a minimum of six years to formulate a composite model for prediction. At the first visit, clinical parameters were collected from routine clinical practice, and circulating markers were assayed from blood. Finding:We constructed the composite predictive model for curve progression to severe Cobb angle > 40° with a high HR of 27.9 (95% CI of 6.55 to 119.16). The area under curve of the composite model is higher than that of individual parameters used in current clinical practice. The model was validated by an independent cohort and achieved a sensitivity of 72.7% and a specificity of 90%. Interpretation:This is the first study proposing and validating a prognostic composite model consisting of clinical and circulating parameters which could quantitatively evaluate the probability of curve progression to a severe curvature in AIS at the initial consultation. Further validation in clinic will facilitate application of composite model in assisting objective clinical decision.
| S-EPMC6948250 | biostudies-literature
Project description:BackgroundThere is considerable discordance in the curve progression of adolescent idiopathic scoliosis (AIS) patients between monozygotic (MZ) twins, indicating that nongenetic factors must be involved in the curve progression of AIS patients. Epigenetic processes may constitute one of these factors and have not yet been investigated in relation to curve progression in AIS patients.MethodsThe genome and methylome of peripheral monocytes were compared between MZ twins discordant for curve progression. Sets of differentially methylated sites were validated using the MassARRAY platform of Sequenome on additional samples.ResultsIn the discovery study, we found evidence suggesting a lack of differences at the genome sequence level and the presence of epigenetic differences related to the curve progression of AIS patients. The top 4 differentially methylated CpG sites associated with curve severity were tested, and only site cg01374129 (CpG site located at chr8:122583383, Hg19) was confirmed in two replication cohorts. The methylation levels of site cg01374129 were significantly lower in the progression group than in the nonprogression group. Cox regression analysis demonstrated that hypo-methylation of site cg01374129 was an independent prognostic factor for curve severity. Site cg01374129 methylation as a marker achieved a sensitivity of 76.4% and a specificity of 85.6% in differentiating between samples from patients with and without curve progression (AUC = 0.827; 95% CI: 0.780 to 0.876).ConclusionIncreased curvature is associated with decreased methylation at site cg01374129. Our results indicate that methylation of site cg01374129 may therefore serve as a promising biomarker in differing between patients with and without curve progression.
| S-EPMC6197569 | biostudies-literature
Project description:Idiopathic scoliosis (IS) is a three-dimensional rotation of the spine >10 degrees with an unknown etiology. Our laboratory established a late-onset IS model in zebrafish (Danio rerio) containing a deletion in kif7. A total of 25% of kif7co63/co63 zebrafish develop spinal curvatures and are otherwise developmentally normal, although the molecular mechanisms underlying the scoliosis are unknown. To define transcripts associated with scoliosis in this model, we performed bulk mRNA sequencing on 6 weeks past fertilization (wpf) kif7co63/co63 zebrafish with and without scoliosis. Additionally, we sequenced kif7co63/co63, kif7co63/+, and AB zebrafish (n = 3 per genotype). Sequencing reads were aligned to the GRCz11 genome and FPKM values were calculated. Differences between groups were calculated for each transcript by the t-test. Principal component analysis showed that transcriptomes clustered by sample age and genotype. kif7 mRNA was mildly reduced in both homozygous and heterozygous zebrafish compared to AB. Sonic hedgehog target genes were upregulated in kif7co63/co63 zebrafish over AB, but no difference was detected between scoliotic and non-scoliotic mutants. The top upregulated genes in scoliotic zebrafish were cytoskeletal keratins. Pankeratin staining of 6 wpf scoliotic and non-scoliotic kif7co63/co63 zebrafish showed increased keratin levels within the zebrafish musculature and intervertebral disc (IVD). Keratins are major components of the embryonic notochord, and aberrant keratin expression has been associated with intervertebral disc degeneration (IVDD) in both zebrafish and humans. The role of increased keratin accumulation as a molecular mechanism associated with the onset of scoliosis warrants further study.
| S-EPMC10218407 | biostudies-literature