Lower WNT16 expression in patients with adolescent idiopathic scoliosis - potential link to lower bone mass in AIS?

Adolescent Idiopathic Scoliosis (AIS) occurs during pubertal rapid growth period and is closely associated with low bone mass. The underlying mechanisms for systemic low bone mass in AIS remains unclear. Wnt signalling pathway is one of the important pathways regulating bone metabolism and influencing bone strength, its family member Wnt16 associates with lower bone mineral density (BMD) in late adulthood, and plays key regulatory role in determining cortical bone quality in adult mice. Our randomized control trial have reported vitamin D (VitD) supplementation significantly improved bone mass and reduced the risk of curve progression in AIS. A case-control study and animal study were employed to answer if WNT16 is associated with the abnormal bone quality in AIS and if the effect of VitD supplementation is associated with Wnt16, respectively. A cohort of 161 AIS and control female subjects were recruited for measurement of anthropometric parameters, bone qualities, and circulating Wnt16 level. In animal study, WT and Wnt16 gKO mice were both subjected to special VitD diet from week 4 and terminated at week 7 and 10 for samples harvesting. AIS showed significantly lower BMD, circulating WNT16 level, and elevated serum level of type I procollagen N-terminal propeptide. Wnt16 gKO mice demonstrated lower cortical bone density compared with WT mice from week 7 of age and Wnt16 gKO were less prone to cortical bone loss induced by high dosage VitD diet. Further study on the biological role of WNT16 and crosstalk with VitD metabolism on bone qualities is warranted which might shed light on prognostic gene of osteopenia and new perspectives for potential target to prevent curve progression.

A six years longitudinal cohort study on the changes in bone density and bone quality up to peak bone mass in adolescent idiopathic scoliosis (AIS) with and without 2 years of Calcium and Vit-D supplementation.

Adolescent idiopathic scoliosis (AIS) is associated with osteopenia which could persist into adulthood affecting attainment of Peak Bone Mass thus resulting in osteoporosis in late adulthood. We previously reported a randomized double-blinded placebo-controlled trial(the Cal study) showing significant bone health improvement with 2-year calcium(Ca)+Vit-D supplementation for AIS girls. This study addressed the important issue whether bone health improvement from the initial 2-year Ca+Vit-D supplementation could persist as subjects approached towards Peak Bone Mass at 6-year ie after 4-year of supplement discontinuation. This was an extension of the Cal study on AIS girls (11-14 years old, mean age=12.9 years, Tanner stage

Role of differentially expressed LBX1 in Adolescent Idiopathic Scoliosis (AIS) paraspinal muscle phenotypes and muscle-bone crosstalk through modulating myoblasts.

AIS is three-dimensional spinal deformity with unclear etiopathogenesis. LBX1 is so far the only multi-centers validated AIS predisposing gene. The imbalance of posterior paraspinal muscles is an important factor in AIS etiopathogenesis. It is poorly understood how LBX1 contributes to the abnormal paraspinal muscles and onset/progression of AIS. We aimed to evaluate the expression of LBX1 in paraspinal muscles at the concave and convex side in AIS, and whether alternation of LBX1 expression could affect myoblastsactivities and potentially influence muscle-bone interaction via myokines expression. Paraspinal muscles from AIS and age- and curvature-matched congenital scoliosis (CS) patients were collected for fiber types analysis. Biopsies were also subjected to qPCR to validate expression of myogenic markers, selected myokines and LBX1. Human skeletal muscle myoblast (HSMM) was used for LBX1 loss-of-function study in vitro. Muscle fiber types analysis showed type I and type IIX/IIAX fibers proportion were significantly different between AIS concave and convex but not in two sides of CS. LBX1, myogenic markers and one myokine were significantly imbalanced in AIS but not in CS. Loss-of-function study showed knockdown of LBX1 could inhibit myogenic markers expression and myokines as well. This study provides new insight into the association between imbalanced paraspinal muscle and potential muscle-bone crosstalk in AIS patients and the biological function of predisposing gene LBX1. Further investigation with appropriate animal models is warranted to explore if asymmetric expression of LBX1 could result in distinct muscle phenotypes and bone qualities thus affect the progression of spine curvature in AIS.

Morphological changes of intervertebral disc in relation with curve severity of patients with Adolescent Idiopathic Scoliosis - a T2-weighted MRI study.

The purpose of this study was to evaluate the morphological changes of intervertebral discs (IVD) and vertebral bodies (VB) in AIS girls according to the subgroups with different curve severity by magnetic resonance imaging (MRI). This study included 33 age-matched female controls and 76 AIS girls with a right-sided thoracic curvature. Wedge angle, height ratio and distance ratio of VB and IVD were measured on the best midline coronal and sagittal planes from reformatted MRI spine. Volumes of VB, IVD and nucleus pulposus (NP) were evaluated on volumetric images. One-way ANOVA with Bonferroni correction was used. There was significant difference in wedge angle and height ratio of VB and IVD between AIS and controls. In severe-AIS, the position of NP was significantly shifted to the convexity when compared with non-severe AIS and controls. Whereas, the volume of IVD and NP in severe-AIS was found to be significantly smaller. On top of coronal wedging of VB and IVD, there was significantly reduced volume of IVD and NP in severe-AIS patients, despite T2 signal of IVD was preserved. The current findings indicate that early mechanical effects on the discs and vertebrae in adolescent scoliotic spine is evident on quantitative imaging. Importantly, these patients may be vulnerable to disc degeneration if no operative treatment is prescribed.

Is ultrasound accurate for radiation-free quantitative assessment of spinal curvatures in patients with idiopathic scoliosis - a systematic review and meta-analysis.

Despite application of ultrasound for quantitative measurement of spinal curvatures has been reported with various studies, a systematic review for such is lacking. This systematic review aimed to evaluate (1) reliability of ultrasound; (2) validity of ultrasound using radiographic measurement as gold standard in idiopathic scoliosis patients; and (3) the use of various anatomical landmarks for measurement of spinal curvatures. MEDLINE, EMBASE, CINAHL, and CENTRAL databases were searched. QUADAS-2 quality assessment tool was adopted. Reliability of ultrasound in terms of intra-class correlation coefficient was recorded. Pearson correlation coefficients between ultrasound and radiographic measurements were extracted for meta-analysis. Subgroup analyses based on ultrasound measurement protocols of spinous process (SP), transverse processes (TP) and center of lamina (COL) were conducted. Eleven articles reporting 18 correlation analyses on 766 subjects were eligible for meta-analysis. The mean inter-rater reliability of ultrasound measurement was 0.87±0.07. Pooled correlation for all studies was 0.918 (95% CI: 0.868-0.949), exhibiting substantial heterogeneity (I2=90.50%, p<0.001). Subgroup analyses showed that pooled correlations were 0.887 for COL method (comprising 356 subjects); 0.924 for SP method (255 subjects); and 0.941 for TP method (117 subjects); all with notable heterogeneity (I2>90%, p<0.001). The overall risk of bias was rated moderate; yet publication bias was noted. Evidences showed that ultrasound was a promising non-invasive method with satisfactory validity and reliability for measuring coronal curvatures utilizing the SP, TP or COL methods. Further development of three-dimensional ultrasound towards scoliosis assessment will facilitate its translational application for managing scoliosis.

Using ultrasound for screening scoliosis to reduce unnecessary radiographic radiation - a prospective diagnostic accuracy study on 442 schoolchildren.

Scoliosis screening is important for timely initiation of brace treatment to mitigate curve progression in skeletally immature children. Scoliosis screening programs frequently include the protocol of referring children screened positive with Scoliometer and Moiré Topography for confirmatory standard radiography. Despite being highly sensitive (88%) for detecting those who require specialist referral, the screening program was found to have more than 50% false positive rate that leads to unnecessary radiation exposure. Radiation-free ultrasound has been reported to be reliable for quantitative assessment of scoliosis curves. The aim of this prospective diagnostic accuracy study was to determine the accuracy of ultrasound in determining the referral status for children initially screened positive for scoliosis. 442 schoolchildren with a mean Cobb angle of 14.0 ± 6.6° were recruited. Using x-ray as the gold standard, the sensitivity and specificity of ultrasound in predicting the correct referral status were 92.3% and 51.6% respectively. ROC curve analysis revealed an area under curve of 0.735 for ultrasound alone and 0.832 for ultrasound plus scoliometer measurement. The finding provided strong evidences on the accuracy of ultrasound in determining the referral status that could result in more than 50% reduction of unnecessary radiation exposure for children undergoing scoliosis screening.