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Exercise in later life is important for bone health and delays the progression of osteoporotic bone loss. Osteocytes are the major bone cells responsible for transforming mechanical stimuli into cellular signals through their highly specialized lacunocanalicular networks (LCN). Osteocyte activity and LCN degenerate with aging, thus might impair the effectiveness of exercise on bone health; however, the underlying mechanism and clinical implications remain elusive. Herein, we showed that deletion of Sirt3 in osteocytes could impair the formation of osteocyte dendritic processes and inhibit bone gain in response to exercise in vivo. Mechanistic studies revealed that Sirt3 regulates E11/gp38 through the protein kinase A (PKA)/cAMP response element-binding protein (CREB) signaling pathway. Additionally, the Sirt3 activator honokiol enhanced the sensitivity of osteocytes to fluid shear stress in vitro, and intraperitoneal injection of honokiol reduced bone loss in aged mice in a dose-dependent manner. Collectively, Sirt3 in osteocytes regulates bone mass and mechanical responses through the regulation of E11/gp38. Therefore, targeting Sirt3 could be a novel therapeutic strategy to prevent age-related bone loss and augment the benefits of exercise on the senescent skeleton.

Abnormal energy metabolism such as lower body weight and body mass index (BMI) and less fat mass is widely reported in patients with adolescent idiopathic scoliosis (AIS) and has been implicated in deformity development. However, the underlying mechanism is largely unclear. LBX1 is one of the promising AIS predisposing genes validated by multicenter studies.This study aimed to identify differentially expressed proteins (DEPs) relating to energy metabolism in AIS by using proteomic and metabolic analysis and to explore if the expression of these DEPs is associated with clinical parameters and modulated by LBX1.This is a cross-sectional study using clinical data and biological samples followed by basic study using a cellular model.Plasma samples were collected from Chinese girls with nonprogressive and progressive AIS (N=7 and 8, respectively) and age-matched healthy girls (N=50). Paraspinal muscle tissues were collected intraoperatively from concave and convex side of the apex of the major spinal curve in AIS (N=24) and either side from nonscoliosis patients (N=14).Radiological Cobb angle and basic anthropometric data of recruited subjects were measured. The DEPs and metabolites were compared in plasma using proteomics and metabolomics technique. The relative expression of selected genes was measured in muscles.Plasma samples from AIS were collected at first clinical visit and were further divided into nonprogressive or progressive groups according to Cobb angle changes in 6-year follow-up. Age-matched healthy girls were recruited as control. High-performance liquid chromatography-mass spectrometry based proteomic analysis was carried out in three groups to identify DEPs and their annotated metabolic pathways. An independent cohort was used for validation by gas chromatography-mass spectrometry based metabolomic analysis. Paraspinal muscles were subjected to quantitative polymerase chain reaction (qPCR) followed by correlation analysis. Human skeletal muscle myoblast (HSMM) was used as the cellular model.The likelihood of aberrant galactose metabolism and glycolysis was found to be associated with AIS curve progression as evidenced by the thirteen DEPs and seven related metabolites according to proteomic and metabolomic analysis. Some of the DEPs showed significantly altered expression in AIS concave and convex sides paraspinal muscles compared with those in nonscoliosis control. Four DEPs were found significantly and negatively correlated with LBX1 in AIS convex side paraspinal muscles. Overexpressing LBX1 in HSMM cells led to increased expression of three DEPs and decreased expression of three DEPs, respectively.This is the first integrated proteomic and metabolomic analysis on AIS. Our findings show dysregulated galactose metabolism and glycolysis pathways in progressive group of AIS, suggesting the presence of abnormal energy metabolism at early stage of this disease, and their association with higher risk of progressing into more severe curvature. Evidence from ex vivo study with human muscle biopsies and in vitro study with human myoblast cells propose the possible effect of LBX1 on these two pathways in skeletal muscles. The present study provides new evidence of LBX1 function in AIS via modulating effect on the expression of energy metabolism related genes. This study might provide new insights into etiopathogenesis and development of novel treatment strategy targeting on abnormal body weight and BMI in patients with AIS. Additionally, the plasma proteomic and metabolomic studies suggested new candidates as biomarkers for establishing predictive model for AIS onset/progression.

The global alignment and proportion (GAP) score was established based on American and European subjects, which might limit its applicability to the Chinese population due to ethnicity-related difference of sagittal alignment.To analyze the applicability of GAP score in the Chinese population and to investigate the age- and gender-associated differences of spinopelvic and GAP score parameters.A prospective cross-sectional radiographic study.Of 692 asymptomatic Chinese volunteers aged between 20 and 79 prospectively recruited between January 2017 and June 2019, 490 subjects were eventually included in this study.The pelvic incidence (PI), pelvic tilt (PT), sacral slope (SS), L1-S1 lordosis, L4-S1 lordosis, sagittal vertical axis (SVA), T1 pelvic angle (TPA) and global tilt (GT) were measured on lateral X-rays. The GAP scores and its parameters including relative pelvic version (RPV), relative lumbar lordosis (RLL), lordosis distribution index (LDI) and relative spinopelvic alignment (RSA) were calculated for each subject.Subjects were divided into four groups: Group 1M: male subjects60 years old; Group 1F: female subjects60 years old; Group 2M: male subjects ≥60 years old and Group 2F: female subjects ≥60 years old. The GAP scores and categories were determined and compared between groups. The results of sagittal alignment were compared with the previous studies evaluating the normative sagittal alignment in other populations. Univariate linear regression analysis was carried out between pelvic incidence (PI) and sacral slope (SS), lumbar lordosis (LL) and global tilt (GT) in each group.The distributions of GAP categories and the updated Roussouly classification were statistically different from other populations. Significantly different distribution of GAP categories was observed between Group 1M and Group 2M, Group 1F and Group 2F, and Group 1M and Group 1F. Radiographic measurements and GAP parameters were significantly different between Group 1M and Group 2M, and Group 1F and Group 2F. Gender-related difference of parameters was more prominent between Group 1M and Group 1F. Linear relationship of PI with SS, LL and GT were different from the regression models of "ideal" sagittal alignment in GAP score.The GAP score might be inappropriate in Chinese population due to ethnicity-related alignment difference. Worse feasibility of GAP score was observed in female and old subjects.

BACKGROUND: Adolescent idiopathic scoliosis (AIS) patients suffer from restrictive impairment of pulmonary function (PF) as a consequence of spinal and ribcage deformity. Statistic modelling of scoliotic geometry has been well-established based on low-dose biplanar X-ray device (EOS) imaging. However, the postoperative lung morphology change derived from EOS has not yet been studied adequately till now. METHODS: Twenty-five female AIS patients with severe right-sided major thoracic curve (aged 13–31 years; Cobb angle 45°–92°) underwent posterior spinal fusion (PSF) were prospectively recruited for standing EOS imaging at preoperative, postoperative, and 1-year follow-up (1Y-FU) stages. EOS-based lung morphology at frontal and lateral view was measured respectively to assess serial statistical changes in area and height. RESULTS: At frontal view, left lung area significantly increased postoperatively (104.7 vs. 125.1 cm(2); P0.05). At lateral view, the increase in left lung area was slight without statistically difference (median: 175.8, 178.4, 182.5 cm(2) at preoperative, postoperative, 1Y-FU stage, respectively; all P>0.05), while right lung area did not significantly change postoperatively (median: 209.9, 206.7, 212.4 cm(2) at preoperative, postoperative, 1Y-FU stage, respectively; all P>0.05). At both frontal and lateral view, left lung height significantly improved at both postoperative and 1Y-FU stage (all P0.05). CONCLUSIONS: EOS imaging demonstrates that left lung area in severe AIS may improve after PSF surgery. EOS may provide useful information about lung morphology change after PSF in severe AIS.

Introduction: A total of 0.1–0.8% of AIS patients progress to severe stages without clear mechanisms, and AIS girls are more prone to curve progression than boys. Recent studies suggest that AIS girls have systemic and persistent low bone-mineral density (BMD), which has been shown to be a significant prognostic factor of curve progression in AIS. The present study aimed to (a) investigate the prevalence of low BMD in patients with severe AIS and (b) assess the sexual dimorphism and independent risk factors of low BMD in severe AIS patients. Materials and Methods: A total of 798 patients (140 boys vs. 658 girls) with AIS who reached surgical threshold (Cobb ≥ 40°) were recruited. BMD were assessed using BMD Z-scores from dual-energy X-ray absorptiometry (DXA). Demographic, clinical, and laboratory values of the subjects were collected from their medical records. Logistic regression analysis was performed to identify independent risk factors of low BMD. Results: The overall prevalence of BMD Z-score ≤ −2 and ≤ −1 were 8.1% and 37.5%, respectively. AIS boys had significantly lower BMD Z-scores (−1.2 ± 0.96 vs. −0.57 ± 0.92) and higher prevalence of low BMD (Z-score ≤ −2: 22.1% vs. 5.2%, p < 0.001; Z-score ≤ −1: 59.3% vs. 32.8%, p < 0.001) than girls. Sex, BMI, serum alkaline phosphatase, and potassium were independent factors of low BMD in the severe AIS patients. Conclusions: The present large cohort of surgical AIS patients revealed that low BMD is more prevalent and severe in boys than in girls with severe curves. Low BMD may serve as a more valuable predictive factor for curve progression to the surgical threshold in boys than girls with AIS.

Abnormal osteocyte lacunar morphology in adolescent idiopathic scoliosis (AIS) has been reported while the results were limited by the number of osteocyte lacunae being quantified. The present study aimed to validate previous findings through (a) comparing morphological features of osteocyte lacunae between AIS patients and controls in spine and ilium using a large-scale assessment, and (b) investigating whether there is an association between the acquired morphological features of osteocyte lacunae and disease severity in AIS.Trabecular bone tissue of the facet joint of human vertebrae on both concave and convex sides at the apex of the scoliotic curve were collected from 4 AIS and 5 congenital scoliosis (CS) patients, and also at the same anatomic site from 3 non-scoliosis (NS) subjects intraoperatively. Trabecular bone tissue from ilium was obtained from 12 AIS vs 9 NS subjects during surgery. Osteocyte lacunae were assessed using ultra-high-resolution micro-computed tomography. Clinical information such as age, body mass index (BMI) and radiological Cobb angle of the major curve were collected.There was no significant difference between density of osteocyte lacuna and bone volume fraction (BV/TV) between groups. A total of 230,076 and 78,758 osteocyte lacunae from facet joints of apical vertebra of scoliotic curve and iliac bone were included in the analysis, respectively. In facet joint bone biopsies, lacunar stretch (Lc.St) was higher, and lacunar equancy (Lc.Eq), lacunar oblateness (Lc.Ob), and lacunar sphericity (Lc.Sr) were lower in AIS and CS groups when compared with NS group. CA side was associated with higher Lc.St when compared with CX side. In iliac bone biopsies, Lc.Ob was higher and lacunar surface area (Lc.S) was lower in AIS group than NS group. Median values of Lc.St, Lc.Eq and Lc.Sr were significantly associated with radiological Cobb angle with adjustment for age and BMI (R-squared: 0.576, 0.558 and 0.543, respectively).This large-scale assessment of osteocyte lacunae confirms that AIS osteocyte lacunae are more oblate in iliac bone that is less influenced by asymmetric loading of the deformed spine than the vertebrae. Shape of osteocyte lacunae in iliac bone is associated with radiological Cobb angle of the major curve in AIS patients, suggesting the likelihood of systemic abnormal osteocyte morphology in AIS. Osteocyte lacunae from concave side of scoliotic curves were more stretched in both AIS and CS groups, which is likely secondary to asymmetric mechanical loading.

This review aimed to systematically review and meta-analyze the effects of interventions in improving bracing compliance among adolescent idiopathic scoliosis (AIS) patients. Eight databases were searched from their inception to April 2022. The eligibility criteria included controlled studies that used any type of intervention to enhance bracing compliance in braced AIS patients. Two researchers independently screened articles and extracted data based on the PICO (participant, intervention, comparator, and outcome) framework. Quality appraisal of included studies was performed using GRADE (overall assessment), and the risk of bias was assessed with Cochrane RoB Tool 2 for randomized controlled trials (RCT) and ROBINS-I for non-RCT studies. The primary outcome was bracing compliance and secondary outcomes included Cobb Angle and measurements for quality of life. Six eligible studies involving 523 participants were included. All studies were evaluated as low or very low quality with a high risk of bias. Four types of interventions were identified, including sensor monitoring (n = 2, RCTs), auto-adjusted brace (n = 1, RCT), more intensive or collaborated medical care (n = 2), and psychosocial intervention (n = 1). A meta-analysis of 215 patients from the three RCTs suggested that the compliance-enhancing intervention group had 2.92 more bracing hours per day than the usual care control (95%CI [1.12, 4.72], P = 0.001). In subgroup analysis, sensor monitoring significantly improved bracing wearing quantity compared to usual care (3.47 hours/day, 95%CI [1.48, 5.47], P = 0.001), while other aforementioned interventions did not show a significant superiority. Compliance-enhancing interventions may be favorable in preventing curve progression and promoting quality of life, but the improvements cannot be clarified according to limited evidence. In conclusion, although the results of this study suggested that sensor monitoring may be the most promising approach, limited high-quality evidence precludes reliable conclusions. Future well-designed RCTs are required to confirm the actual benefit of compliance-improving interventions in clinical practice.

Background Our previous studies found disproportionate anteroposterior vertebral size is associated with severity of the scoliotic curves in adolescent idiopathic scoliosis (AIS) patients. Subsequent studies showed wedging of vertebral bodies (VB) had less contribution than intervertebral discs (IVD) to the anterior–posterior vertebral column length discrepancy in severe-AIS. However, the exact morphological changes of IVD were not clearly defined. This study aimed to evaluate the morphological and pathological changes of IVD and VB in AIS girls and healthy female controls. Methods 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 also evaluated on volumetric images. One-way ANOVA with Bonferroni correction and Pearson correlation tests were used. Results 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. In addition, Cobb angle was significantly correlated with wedge angle and height ratio, and inversely correlated with the volume of NP. Conclusions In addition to wedging of VB and IVD, there was significantly reduced volume of IVD and NP in AIS patients with severe curve, insinuating the mechanical effect of scoliosis leads to a compression on both IVD and NP before significant disc desiccation occurs. We postulate that the compression of IVD and NP can contribute to curve progression in severe-AIS, these patients are more prone to disc degeneration in adulthood if no operative treatment is offered. Further longitudinal study on these parameters is still warranted.

Adolescent idiopathic scoliosis (AIS) is a three-dimensional deformity of the spine. Spine slenderness, which represents its potential instability to buckling under compressive loads, was shown to be higher in AIS patients than non-scoliotic subjects, but it is not clear at what stage of the progression this difference appeared, nor if slenderness could be used as an early sign of progression. In this study, we hypothesized that slenderness could be an early sign of progression. One-hundred thirty-eight patients and 93 non-scoliotic subjects were included. They underwent standing biplanar radiography and 3D reconstruction of the spine, which allowed computing vertebra and disc slenderness ratio. Then, patients were followed until progression of the deformity or skeletal maturity (stable patients). Vertebral slenderness ratio in AIS patients varied between 2.9 [2.7; 3.0] (T9) and 3.4 [3.2; 3.6] (T1), while disc slenderness ranged from 0.6 [0.6; 0.7] at T6-T7 to 1.2 [1.1; 1.3] at L4-L5. Slenderness ratio increased with age, while disc slenderness tended to decrease with age and Cobb angle. Slenderness was similar between progressive and stable patients, and also between patients and non-scoliotic subjects. In conclusion, spinal slenderness does not appear to be an early sign of progression. Further studies should analyse the development of slenderness during growth, and how it could be affected by non-operative treatment.

Background: Balanced global spinopelvic balance is important in the maintenance of the physiological alignment of all body segments above the pelvis with minimum energy expenditure. The key determinants affecting the 3D index-odontoid-hip axis (OD-HA) angle, and in particular its alterations, have not been clearly defined. The aim of this study is to identify the determinants of the 3D OD-HA angle in maintaining global spinopelvic balance in a large Chinese adult cohort of different gender and age groups. Methods: A total of 516 asymptomatic adults were enrolled in this study. Biplanar radiographies were performed to reconstruct the subject’s inter-acetabular axis and C2 odontoid process. The 3D angle formed by the vertical and the line between odontoid and mid-interacetabular axis (OD-HA angle) was computed and projected in the subject’s sagittal and coronal planes. Thoracic kyphosis (TK), lumbar lordosis (LL), T1 pelvic angle (TPA) and sagittal vertical axis (SVA) were measured. Results: The mean values of sagittal and coronal OD-HA were −0.2°±2.5° and 0.2°±1.1°, respectively. Both sagittal and coronal OD-HA had significant correlation with age (r=0.265 and r=−0.143, P

A genetic association study.To investigate the association between PAX1 gene and the susceptibility of adolescent idiopathic scoliosis (AIS) in the Chinese population and to further determine the functional variant regulating PAX1 expression in patients with AIS.In a previous study an enhancer locus of PAX1 was reported to be associated with the development of AIS in the Caucasian and the Japanese population. However, there is a paucity of knowledge concerning the functional role of PAX1 in the Chinese AIS population.The single-nucleotide polymorphisms rs6137473 and rs169311 were genotyped in 2914 patients and 3924 controls. The differences of genotype and allele distributions between patients and controls were calculated using chi-square test. Paraspinal muscles were collected from 84 patients with AIS. The one-way analysis of variance test was used to compare the mRNA expression of PAX1 among different genotypes.Both rs6137473 and rs169311 were significantly associated with the susceptibility of AIS. Allele G of rs6137473 and allele A of rs169311 can significantly add to the risk of AIS with an odds ratio of 1.17 and 1.22, respectively. Moreover, there was significant difference regarding the expression of the PAX1 between the concave side and convex side of the patients. Patients with genotype AA of rs169311 had significantly decreased expression of PAX1 than those with genotype CC. As for rs6137473, no remarkable difference of PAX1 expression was found among the three genotypes.The association between PAX1 and the susceptibility of AIS was successfully replicated in the Chinese population. Moreover, rs169311 could be a functional variant regulating the expression of PAX1 in the paraspinal muscles of AIS. Further functional analysis is warranted for a comprehensive knowledge on the contribution of this variant to the development of AIS.3.