Hiu-Yan Yeung

Phytoestrogen-rich herb formula XLGB prevents OVX-induced deterioration of musculoskeletal tissues at the hip in old rats

This study investigated a phytoestrogen-rich herb formula, Xianlinggubao (XLGB) μncluding genistein 510μg/g and daidzein 2500μg/g), concerning prevention of OVX-induced deterioration of musculoskeletal tissues in 11-month-old female Wistar rats, which were randomized into Sham, OVX, and XLGB groups. Daily oral administration of XLGB (250mg/kg/day) started after OVX for 3 months. mRNA of MHC-I IIa IIb of abductor muscle was determined by RT-PCR. The proximal femoral BMD and geometry, microarchitecture, and mechanical strength were evaluated by pQCT, micro-CT, and compressive testing, respectively. The bone turnover biochemical markers serum osteocalcin (OC) and urinary deoxypyridinoline (DPD) were evaluated. The results showed that (1) XLGB-treated OVX rats showed no difference compared to the Sham group, whereas OVX induced significant deterioration in variables related to bone density, microarchitecture, and mechanical strength (P < 0.05); (2) biochemical markers showed no difference between sham and XLGB groups as compared with higher bone turnover in OVX rats (P < 0.05); (3) mRNA expression of MHC-I IIa IIb was downregulated in OVX rats but upregulated after XLGB treatment (P < 0.05); and (4) as compared with the OVX group, no uterine hypertrophy was found in XLGB-treated rats. In conclusion, findings of this study suggested that the herbal preparation XLGB was able to prevent OVX-induced deterioration of musculoskeletal tissues at the hip without causing uterine stimulation.

A Relook Into the Association of the Estrogen Receptor α Gene (PvuII, XbaI) and Adolescent Idiopathic Scoliosis : A Study of 540 Chinese Cases

Study Design. A genetic association study of estrogen receptor-α gene (ESR1) with adolescent idiopathic scoliosis (AIS) in Chinese. Objectives. To investigate whether: 1) PvuII and XbaI polymorphisms in ESR1 are predisposition factor for AIS and 2) these polymorphisms correlate with the severity of curvature in AIS. Summary of Background Data. A common single nucleotide polymorphism (SNP) in ESR1 (XbaI) was found to be associated with curve severity in Japanese AIS patients recently. The role of ESR1 as a predisposition gene using a case-control design in other ethnic groups is required to confirm the previous associations. Methods. A total of 540 Chinese AIS girls with Cobb angle above 20° were recruited as cases together with 260 healthy controls. The effect of ESR1 SNPs on severity of scoliosis was analyzed in a subgroup of AIS patients (n = 364) followed up until skeletal maturity with the maximum Cobb angle recorded. Two SNPs in ESR1 were genotyped by PCR-restriction fragment length polymorphism in all subjects. Results. The allelic frequency of X allele was 23% in both case and control groups. The P allele was found at allelic frequency of 40% and 36% in the case and control groups, respectively. No association between the two ESR1 SNPs and the occurrence of AIS by both genotype and haplotype analysis could be established, suggesting that both SNPs were not predisposition alleles for AIS. AIS patients with different genotypes showed no difference in the maximum Cobb angle. No association was found between the genotype and anthropometric measurements in AIS patients. Conclusion. The previously reported association with curve severity could not be replicated in our large series of Chinese AIS patients. The current study also did not show any association of the 2 SNPs with increased risk of having AIS.

Abnormal leptin bioavailability in adolescent idiopathic scoliosis: an important new finding.

Study Design. This was a cross-sectional study. Objective. The present study aimed to explore the differences in leptin bioavailability between adolescent idiopathic scoliosis (AIS) and healthy age-matched girls in a Chinese Han population. Summary of Background Data. AIS is a common spinal deformity mainly occurring in girls during the peripubertal period. The development of scoliosis is related to relative anterior spinal overgrowth. AIS girls also have associated lower body mass index (BMI) and lower bone mineral status. Leptin, together with soluble leptin receptor (sOB-R), was shown to play an important role in the regulation of bone and energy metabolism in children. It was hypothesized that leptin and sOB-R are abnormal and associated with deranged growth and anthropometric phenotypes in AIS girls. Methods. Serum leptin and sOB-R were measured together with documentation of anthropometric parameters and clinical data in 95 AIS girls and 46 healthy matched controls (age 11–16 years). Serum leptin and sOB-R concentrations were measured by enzyme-linked immunosorbent assay and correlated with the different measured parameters. Results. AIS girls had significantly lower BMI and longer arm span than healthy controls. AIS girls were found to have significantly higher sOB-R levels and lower free leptin index (FLI) after adjusting for age and body weight in multivariate regression analysis. Significant correlation was found between sOB-R, FLI, and curve severity in AIS girls. Conclusion. This is the first study demonstrating the presence of abnormal leptin bioavailability in AIS girls that might play an important role in the etiopathogenesis of AIS. Further investigation is required to provide a better understanding of the underlying mechanisms, with the aim to explore the potential clinical application as a biomarker for predicting curve initiation or progression in AIS.

Effect of weightbearing on bone formation during distraction osteogenesis

The effect of weightbearing on the bone formation during distraction osteogenesis was studied with 24 goats after standardized osteotomy and distraction. Twelve goats were allowed to bear weight immediately and 12 were not allowed to bear weight. With the pattern of weightbearing documented, the formation of bone was monitored with serial radiographs and the bone forming activity was studied with histologic examination and immunohistochemical study of transforming growth factor-beta 1 expression. The results of the study showed that the bone formation as depicted by radiologic assessment of callus width and mineralized tissue was significantly better in the weightbearing group. Histologic study showed more bone formation qualitatively and quantitatively in the weightbearing group. This study confirmed the beneficial effect of weightbearing activity during distraction osteogenesis. Distraction provides pulsed form stimulation by tension stress across the osteotomy site and initiates osteogenesis while the compression stress exerted by the weightbearing is continuous in daily activities and enhances new bone formation. The clinical practice of early weightbearing during distraction osteogenesis should be reinforced.

Genetic association study of growth hormone receptor and idiopathic scoliosis.

Although the etiology of scoliosis is multifactorial, genetic factors play an important role. Recent linkage studies on familial idiopathic scoliosis revealed multiple putative predisposition loci. A genetic association study is complementary to linkage studies in defining the genetic basis of complex traits of diseases like idiopathic scoliosis. The onset and progression of adolescent idiopathic scoliosis is a manifestation of aberrant growth in the spine. Meanwhile, a high proportion of patients with adolescent idiopathic scoliosis have additional phenotypes, which suggest systemic growth dys-regulation during puberty. The growth hormone-insulin-like growth factor axis plays the principle role in skeletal growth regulation. Because growth hormone receptor alleles were associated with body stature and response to growth hormone treatment, we hypothesized the growth hormone receptor is a candidate predisposing and disease modifier gene for adolescent idiopathic scoliosis. Five hundred ten girls with adolescent idiopathic scoliosis and 363 normal subjects were recruited. Curve severity, arm span, and bone mineral densities were recorded. Five polymorphisms were studied by polymerase chain reaction-restriction fragment length polymorphism. All the genotype and allele frequencies were comparable between groups. The Cobb angles among patients of different genotypes were similar. The growth hormone receptor did not appear to be a predisposing gene or disease modifier gene of adolescent idiopathic scoliosis.

Abnormal skeletal growth patterns in adolescent idiopathic scoliosis--a longitudinal study until skeletal maturity.

Study Design. A cross-sectional and prospective longitudinal study on the anthropometric parameters and growth pattern of girls with adolescent idiopathic scoliosis (AIS). Objective. To investigate the growth pattern of girls with AIS with different severities, using cross-sectional and prospective longitudinal data set in comparison with age-matched healthy controls. Summary of Background Data. AIS occurs in children during their pubertal growth spurt. Although there is no clear consensus on the difference in body height between girls with AIS and healthy controls, it is generally thought that the development and curve progression in girls with AIS is closely associated with their growth rate. There is no concrete prospective longitudinal study to document clearly the growth pattern and growth rate of subjects with AIS . Methods. A total of 611 girls with AIS and 296 healthy age-matched controls were included in the study and among them, 194 girls with AIS and 116 healthy controls were followed up until skeletal maturity. The girls with AIS were grouped into moderate (AIS20) and severe curve (AIS40) groups on the basis of maximum curve magnitude at skeletal maturity. Clinical data and detailed anthropometric parameters were recorded. In the cross-sectional analysis, the groups of subjects were compared within different age groups (from the age of 12–16 yr). In the longitudinal study, linear mixed modeling with respect to age or years since menarche was employed to formulate the growth trajectory of different anthropometric parameters. Results. In the cross-sectional analysis, the girls with AIS were generally taller, with longer arm span and lower body mass index than the healthy controls. The girls with AIS40 were found to be significantly shorter in height (P = 0.006) and arm span (P = 0.025) at the age of 12 years but caught up and overtook the control group at the age of 14 to 16 years. In the longitudinal study, the average growth rate of arm span in girls with AIS40 was significantly higher than that in girls with AIS20 (> 30%) (P = 0.004) and controls (> 70%) (P = 0.0004). The age of menarche of girls with AIS40 was significantly delayed by 5.9 months and 3.8 months when compared with the control group and girls with AIS20, respectively (P < 0.05). Conclusion. The growth patterns of girls with AIS with confirmed curve severities were significantly different from healthy age-matched controls. Girls with severe AIS had delayed menarche with faster skeletal growth rate during the age of 12 to 16 years. Monitoring the rate of change of arm span of girls with AIS could be an important additional clinical parameter in helping predict curve severity in girls with AIS.

Abnormal bone quality versus low bone mineral density in adolescent idiopathic scoliosis: a case-control study with in vivo high-resolution peripheral quantitative computed tomography

BACKGROUND CONTEXT Adolescent idiopathic scoliosis (AIS) is associated with low bone mass that could persist into early adulthood and is an important prognostic factor for curve progression. Previous studies were confined to areal bone mineral density measurement that was a two-dimensional investigation for a three-dimensional structure. Evaluation of volumetric BMD (vBMD) and other bone quality parameters are important for gaining in-depth understanding of the etiopathogenesis of AIS. PURPOSE The objective of this study was to carry out direct in vivo measurement of bone quality in AIS using high-resolution peripheral quantitative computed tomography (HR-pQCT) and compare the correlation of bone quality with osteopenia between AIS and control subjects. STUDY DESIGN/SETTING A case-control study. PATIENT SAMPLE Newly diagnosed AIS girls (n=112) and non-AIS girls (n=115) between 11 and 13 years. OUTCOME MEASURES Areal bone mineral density of bilateral femoral necks and HR-pQCT of the nondominant distal radius were performed. METHODS Areal bone mineral density of femoral necks was measured by dual-energy X-ray absorptiometry. Subjects were classified into the osteopenic (Z score less than or equal to -1) and nonosteopenic (Z score more than -1) groups. Bone quality parameters, including bone morphometry, trabecular bone microarchitecture, and vBMD, were measured by HR-pQCT (XtremeCT; Scanco Medical, Zurich, Switzerland). RESULTS In AIS, the osteopenic group had lower measurements in cortical area, cortical thickness, average vBMD, compact bone vBMD, trabecular vBMD, trabecular bone volume to tissue volume ratio, and trabecular thickness compared with nonosteopenic AIS subjects. In contrast, among the non-AIS controls, the osteopenic group had lower measurements only in bone morphometry, average vBMD, and compact bone vBMD but not in trabecular vBMD and all other trabecular bone microarchitecture parameters. CONCLUSIONS This is the first study using HR-pQCT to compare the correlation of bone quality with osteopenia in AIS and non-AIS subjects. It provides new insights and highlights the unique bone quality profile with predominant changes in the trabecular compartment in association with osteopenia being notably only detected in the AIS subjects. Further studies in this area are warranted for defining the metabolic nature and biomechanical sequelae of derangement in bone mass and bone quality and their roles in the etiopathogenesis of AIS.

Genetic epidemiology and heritability of AIS: A study of 415 Chinese female patients

Recent familial segregation studies supported a multifactorial genetic model for the etiology of adolescent idiopathic scoliosis (AIS). However, the extent of quantitative genetic effects, such as heritability, have not been fully evaluated. This genetic epidemiology study examined the sibling recurrent risk and heritability of AIS in first‐degree relatives of 415 Chinese female patients, which is up to now the largest cohort. They were first diagnosed by community screening program and compared to 203 age‐matched normal controls. Out of the total 531 sibs of AIS cases, 94 sibs had scoliosis (sibling recurrence risk = 17.7%). The prevalence of AIS among male and female sibs of an index case were 11.5% (95% CI = 7.5–15.5) and 23.0% (95% CI = 18.1–27.9), respectively. Female sibs of an index case had an increased risk of 8.9‐fold (95% CI = 3.2–34.4) for developing AIS. These recurrent risks were significantly higher than the risk in the control group (p < 0.0001). Overall, heritability was estimated to be 87.5 ± 11.1%. The results confirmed the prevailing impression of strong genetic influence on the risk of AIS. Here we provided a large‐scale study for the genetic aggregation estimates in an Asian population for the first time. The finding also positioned AIS among other common disease or complex traits with a high heritability.

Lack of association between the promoter polymorphism of the MTNR1A gene and adolescent idiopathic scoliosis.

Study Design. A genetic association study to investigate variation of the melatonin receptor 1A (MTNR1A) gene in adolescent idiopathic scoliosis (AIS) patients. Objective. To determine whether the MTNR1A gene promoter polymorphism is associated with the predisposition and/or disease severity of AIS. Summary of Background Data. An involvement of the dysfunction of the melatonin pathway in the etiopathogenesis of AIS has been implicated in several studies. Recently, our group has found that the promoter polymorphism of the melatonin receptor 1B (MTNR1B) gene was associated with the occurrence of AIS. Hence, it is of interest to determine whether the promoter polymorphism of the MTNR1A gene could also associated with the occurrence or curve severity of AIS. Methods. A total of 226 AIS girls and 277 normal controls were recruited. SNP rs2119882 in the promoter region (−369 bp) of the MTNR1A gene was selected for the present study. Genotyping was performed by PCR-RFLP. Statistical analysis of genotype frequencies between case and control was performed by &khgr;2 test. One-way ANOVA was used in comparison of mean maximum Cobb angles with different genotypes in case-only analysis. Results. Genotype and allele frequencies were comparable between case and control for SNP rs2119882 (P > 0.05). The mean maximum Cobb angles of different genotypes were similar with each other for SNP rs2119882. Conclusions. Promoter polymorphism of the MTNR1A gene was not associated with the occurrence or curve severity of AIS. The MTNR1A gene may not be involved in the etiopathogenesis of AIS.

Sustained expression of transforming growth factor-β1 by distraction during distraction osteogenesis

Distraction osteogenesis is a well-established clinical treatment for limb length discrepancy and skeletal deformities. In our previous studies, we have shown that the tension at the distraction gap correlated with the plasma bone specific alkaline phosphatase activity during distraction. Transforming growth factor-beta1 (TGF-beta1) has been shown to have a regulatory role in alkaline phosphatase activity during fracture healing. This study is to investigate the expression of TGF-beta1 during distraction as a biological response to mechanically stimulated osteoblastic activity by immunohistochemistry. The expression of TGF-beta1 in the distraction callus was compared with that in the fracture callus. During the distraction phase, the osteoblasts and osteocytes expressed a high level of TGF-beta1. Moderate expression of TGF-beta1 was observed in fibroblast-like cells in the fibrous zone of the distraction callus. After the distraction stopped, the expression of TGF-beta1 in different cell types decreased. In fracture healing, the strong expression of TGF-beta1 declined after the first week. Our results showed that the mechanical force induced and sustained TGF-beta1 expression in osteoblasts and fibroblasts-like cells of the distraction callus. Transforming growth factor-beta1 may play a role in transducing mechanical stimulation to biological tissue during in distraction osteogenesis.