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Pseudoachondroplasia (PSACH; MIM no. 177170) is an autosomal dominant osteochondrodysplasia characterized by short-limb short stature, brachydactyly and early-onset osteoarthropathy. Typically, at approximately two years of age, the rate of growth falls below the standard growth curve, causing a moderately severe form of disproportionate short-limb short stature. The current study described the clinical and radiographic observations of six Chinese patients with PSACH, and identified two de novo novel missense mutations [p.Asp326Asn (c.976G>A) and c.1585A>G (p.Thr529Ala)] in cartilage oligomeric matrix protein (COMP) in the patients. The current study expanded the mutation spectrum of the COMP gene, and contributes to the understanding of phenotype/ genotype of COMP-associated diseases. [ABSTRACT FROM AUTHOR]

Aim:To investigate the effect of low-density lipoprotein receptor-related protein 5 (LRP5) gene polymorphisms on bone and obesity phenotypes in young Chinese men.Methods:A total of 1244 subjects from 411 Chinese nuclear families were genotyped by using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique at the Q89R, N740N, and A1330V sites in the LRP5 gene. Bone mineral density (BMD) in the lumbar spine and the hip, total fat mass and total lean mass were measured using dual-energy X-ray absorptiometry. The association between LRP5 gene polymorphisms and peak BMD, body mass index (BMI), total fat mass, total lean mass and percentage of fat mass was assessed using a quantitative transmission disequilibrium test (QTDT).Results:No significant within-family associations were found between genotypes or haplotypes of the LRP5 gene and peak BMD, BMI, total fat mass, total lean mass and percentage of fat mass. The 1000 permutations that were subsequently simulated were in agreement with these within-family association results.Conclusion:Our results suggest that common polymorphic variations of the LRP5 gene do not influence peak bone mass acquisition and obesity phenotypes in young Chinese men. [ABSTRACT FROM AUTHOR]

AbstractAim:To determine the associations between HOXD4 gene polymorphisms with peak bone mineral density (BMD) throughing measuring three tagging single nucleotide polymorphisms (tagSNPs), including rs1867863, rs13418078, and rs4972504, in HOXD4.Methods:Four hundred Chinese nuclear families with male offspring (1215 subjects) and 401 Chinese nuclear families with female offspring (1260 subjects) were recruited. BMD of the lumbar spine 1-4 (L1-4) and left proximal femur including total hip and femoral neck were measured by dual-energy X-ray absorptiometry. The quantitative transmission disequilibrium test (QTDT) was performed to investigate the association among the tagging SNPs, haplotypes and peak BMD.Results:Only the CC genotype was identified in rs13418078 in the Chinese population, unlike other populations. We failed to find significant within-family association among these SNPs, haplotypes and peak BMD at any bone site in either male- or female-offspring nuclear families.Conclusion:The results suggest that genetic polymorphisms in HOXD4 may not be a major contributor to the observed variability in peak BMD in the lumbar spine and the hip in Chinese men and women. [ABSTRACT FROM AUTHOR]

Background: The Wnt/beta-catenin signaling pathway plays an important role in skeletal development. Polymorphisms of frizzled-related protein (FRZB), an antagonist of this pathway, may generate variations in bone mineral density (BMD). In this study, we analyzed the association between FRZB genotypes and peak BMD variation in the spines and hips of two relatively large samples of Chinese female-offspring and male-offspring nuclear families. Methods: We recruited 1,260 subjects from 401 female-offspring nuclear families and 1,296 subjects from 427 male-offspring nuclear families and genotyped four tagging single nucleotide polymorphisms (tagSNPs) (rs6433993, rs409238, rs288324, and rs4666865) spanning the entire FRZB gene. The SNPs rs288326 and rs7775, which are associated with hip osteoarthritis, were not selected in this study because of their low minor allele frequencies (MAFs) in Chinese people. The quantitative transmission disequilibrium test (QTDT) was used to analyze the association between each SNP and haplotype with peak BMD in female- and male-offspring nuclear families. Results: In the female-offspring nuclear families, we found no evidence of an association between either single SNPs or haplotypes and peak BMD in the spine or hip. In the male-offspring nuclear families, no within-family association was observed for either SNPs or haplotypes, although a significant total association was found between rs4666865 and spine BMD (P = 0.0299). Conclusion: Our results suggest that natural variation in FRZB is not a major contributor to the observed variability in peak BMD in either Chinese females or males. Because ethnic differences in the FRZB genotypes may exist, other studies in different population are required to confirm such results. [ABSTRACT FROM AUTHOR]

AbstractAim:The goal of this study was to determine whether polymorphisms in the vitamin D receptor (VDR) and estrogen receptor alpha (ESR1) genes are associated with variations of peak bone mineral density (BMD) and obesity phenotypes in young Chinese men.Methods:A total of 1215 subjects from 400 Chinese nuclear families were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and allele-specific multiple PCR (ASM-PCR) analysis at the ApaI, FokI, and CDX2 sites in the VDR gene and the PvuII and XbaI sites in the ESR1 gene. BMD at the lumbar spine and hip, total fat mass, and total lean mass were measured using dual energy X-ray absorptiometry. The associations between VDR and ESR1 gene polymorphisms with peak BMD, body mass index (BMI), total fat mass, total lean mass, and percentage fat mass (PFM) were determined using quantitative transmission disequilibrium tests (QTDTs).Results:Using QTDTs, no significant within-family associations were obtained between genotypes or haplotypes of the VDR and ESR1 genes and peak BMD. For the obesity phenotypes, the within-family associations were significant between CDX2 genotypes and BMI (P=0.046), fat mass (P=0.004), and PFM (P=0.020). Further, PvuII was significantly associated with the variation of fat mass and PFM (P=0.002 and P=0.039, respectively). A subsequent 1000 permutations were in agreement with these within-family association results.Conclusion:Our findings showed that VDR and ESR1 polymorphisms were associated with total fat mass in young Chinese men, but we failed to find a significant association between VDR and ESR1 genotypes and peak BMD. These findings suggested that the VDR and ESR1 genes are quantitative trait loci (QTL) underlying fat mass variation in young Chinese men. [ABSTRACT FROM AUTHOR]

AbstractAim:A previous study showed that individuals of Japanese descent affected by early onset familial Paget's disease of bone (PDB) carried a 27-bp duplication at position 75 (75dup27) in the TNFRSF11A gene encoding RANK. Here we report the identification of a novel mutation (78dup27) in exon 1 of TNFRSF11A in a Chinese family with early onset PDB.Methods:We conducted clinical and genetic studies in a non-consanguineous Chinese family with early onset PDB. The entire coding region of TNFRSF11A was amplified and directly sequenced directly.Results:A novel 27-bp duplication in exon 1 (78dup27) in TNFRSF11A was found in four affected individuals and one asymptomatic individual. Although this duplication was the same length as the previously identified mutation (27 bp, from bases 78 to 104), in our patients the nine duplicated amino acids in the RANK signal peptide were LLLLCALLA. The phenotypes of affected individuals in this family overlapped with both early onset PDB and classic PDB, but several distinguishing features were found in our patients. The key difference between our familial PDB and the Japanese early onset PDB was the age of onset, which in most of our patients was during their late 20s (except for the propositus' niece). Another notable difference was that the propositus' son (24 years old), who carried the 78dup27 mutation, had no clinical symptoms or bone abnormalities, except for increased serum ALP, OC and CTX.Conclusion:Our findings may provide a better understanding of the clinical features of early onset PDB and support the notion of a hot spot for mutations in exon 1 of the TNFRSF11A gene.Acta Pharmacologica Sinica (2009) 30: 1204–1210; doi: 10.1038/aps.2009.90; published online 6 July 2009 [ABSTRACT FROM AUTHOR]

Aim: Osteoclastic activity is mainly assessed by measurement of urinary markers ( eg C-terminal cross-linked telopeptides of type I collagen, N-terminal cross-linked telopeptides of type I collagen etc), the levels of which could often be affected by renal clearance. Recently, serum tartrate-resistant acid phosphatase 5b (TRACP5b) has been used as an alternative serum marker to evaluate osteoclastic activity. We investigated the age-related changes of TRACP5b level and its association with bone mineral density (BMD) in Chinese women. Methods: Seven-hundred and twenty-two Chinese mainland women aged 20–79 years were recruited in the study. Serum TRACP5b level was measured using immunoassay to evaluate the state of bone resorption. Bone mineral density (BMD) (g/cm2) at lumbar spine 1–4 and proximal femur were measured by duel-energy X-ray absorptiometry. Results: The serum TRACP5b level reached a bottom value in premenopausal women aged 30–39, gradually increased in women aged 40–49, rapidly rose in women aged 50–59, and culminated with a maximum value in women aged 60–69 before a slow drop in women aged 70–79. The average level of TRACP5b was significantly higher in postmenopausal women [(3.29±1.07) U/L] than in premenopausal women ([1.70±0.59] U/L). The levels of TRACP5b were inversely correlated with BMD at all measured sites ( P<0.001). Furthermore, the level of TRACP5b was obviously higher in women with osteoporosis and osteopenia than those with normal bone mass ( P<0.001). Conclusion: We have established the reference values of serum TRACP5b in Chinese mainland women, and found that postmenopausal women had higher TRACP5b concentration than younger women. The results showed that serum TRACP5b was a sensitive and useful parameter for the evaluation of age-related changes of bone absorption. [ABSTRACT FROM AUTHOR]

Aim: To assess the contribution of single nucleotide polymorphisms (SNP) and haplotypes in the peroxisome proliferator-activated receptor-γ co-activator-1 (PPARGC1) and adiponectin genes to normal bone mineral density (BMD) variation in healthy Chinese women and men. Methods: We performed population-based (ANOVA) and family-based (quantitative trait locus transmission disequilibrium test) association studies of PPARGC1 and adiponectin genes. SNP in the 2 genes were genotyped. BMD was measured using dual-energy X-ray absorptiometry in the lumbar spine and hip in 401 nuclear families with a total of 1260 subjects, including 458 premenopausal women, 20–40 years of age; 401 post-menopausal women (mothers), 43–74 years of age; and 401 men (fathers), 49–76 years of age. Results: Significant within-family association was found between the Thr394Thr polymorphism in the PPGAGC1 gene and peak BMD in the femoral neck ( P=0.026). Subsequent permutations were in agreement with this significant within-family association result ( P=0.016), but Thr394Thr SNP only accounted for 0.7% of the variation in femoral neck peak BMD. However, no significant within-family association was detected between each SNP in the adiponectin gene and peak BMD. Although no significant association was found between BMD and SNP in the PPARGC1 and adiponectin genes in both men and postmenopausal women, haplotype 2 (T-T) in the adiponectin gene was associated with lumbar spine BMD in postmenopausal women ( P=0.019). Conclusion: Our findings suggest that Thr394Thr SNP in the PPARGC1 gene was associated with peak BMD in the femoral neck in Chinese women. Confirmation of our results is needed in other populations and with more functional markers within and flanking the PPARGC1 or adiponectin genes region. [ABSTRACT FROM AUTHOR]

Aim: To construct an A20 expression vector under the control of mouse osteocalcin promoter (OC-A20), and investigate osteoblastic MC3T3-E1 cell line, which stably overexpresses A20 protein prevented tumor necrosis factor (TNF)-alpha-induced apoptosis. Methods: OC-A20 vector was constructed by fusing a fragment of the mouse osteocalcin gene-2 promoter with human A20 complementary DNA. Then the mouse MC3T3-E1 cell line, stably transfected by A20, was established. The expression of A20 mRNA and A20 protein in the cells were detected by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis, respectively. To determine the specificity of A20 expression in osteoblast, the mouse osteoblastic MC3T3-E1 cell line and mouse embryo fibro-blast NIH3T3 cell line were transiently transfected with OC-A20. The anti-apoptotic role of A20 in MC3T3-E1 cells was determined by Flow cytometric analysis (FACS), terminal dUTP nick endo-labeling (TUNEL) and DNA gel electrophoresis analysis (DNA Ladder), respectively. Results: Weak A20 expression was found in MC3T3-E1 cells with the primers of mouse A20. A20 mRNA and A20 protein expression were identified in MC3T3-E1 cells transfected with OC-A20 using RT-PCR and Western blot analysis. Only A20 mRNA expression was found in MC3T3-E1 cell after MC3T3-E1 cells and NIH3T3 cells were transient transfected with OC-A20. A decrease obviously occurred in the rate of apoptosis in the OC- A20 group compared with the empty vector (pcDNA3) group by FACS ( P<0.001). A significant increase in TUNEL positive staining was found in the pcDNA group compared with OC-A20 group ( P<0.001). Simultaneously, similar effects were demonstrated in DNA gel electrophoresis analysis. Conclusion: We constructed an osteoblast-specific expression vector that expressed A20 protein in MC3T3-E1 cells and confirmed that A20 protects osteoblast against TNF-alpha-induced apoptosis. [ABSTRACT FROM AUTHOR]

Aim: To establish bone mineral density (BMD) reference database in healthy Chinese men of Han ethnicity, and to estimate the prevalence of osteoporosis in the population. Methods: The BMD in the lumbar spine 1-4 (L1-4) and proximal femur was measured using dual energy X-ray absorptiometry in a total of 1 385 healthy Chinese men of Han ethnicity aged 20–89 years old in Shanghai. Results: The highly significant negative correlation between age and BMD at any sites of proximal femur was found in the studied population, wheras no correlation between age and BMD at lumbar spine was observed. The peak BMD of the lumbar spine and any sites of hip in Chinese men was defined as the mean BMD for the subjects aged 20–39 years. According to World Health Organization (WHO) criteria, the BMD cut-off values for osteoporosis of the L1-4, total hip, femoral neck, trochanter and intertrochanter in Chinese men are 0.719, 0.638, 0.575, 0.437 and 0.725 g/cm2, respectively. Using the current Chinese reference data, the prevalence of osteoporosis at the L1-4, total hip, femoral neck, trochanter and intertrochanter is 5.4%, 3.8%, 6.3%, 1.8% and 2.8% in 1 084 men aged 50 years or older, respectively. However, using a database for US non-Hispanic white men (NHANES III), the prevalence of osteoporosis or osteopenia at any sites of the hip was significantly higher than that while using the current Chinese reference data. Conclusion: The BMD reference database was established in healthy Chinese men of Han ethnicity, and will facilitate more accurate diagnosis of osteoporosis in Chinese men. [ABSTRACT FROM AUTHOR]

Objective This paper aims at supplying a scientific basis for unifying the normal reference value standard forced vital capacity of Chinese younger men. Methods The research is made to study the relationship between the normal reference value of 25,393 examples of forced vital capacity of younger men and eight geographical factors in 304 areas in China. Results It is found that the correlation of geographical factors and the normal reference value of forced vital capacity of younger men is quite significant (F = 84.831, P = 0.000). By adopting the methods of mathematical regression analysis, one regression equation is inferred; Y = 5.404 + 0.0002371X1 - 0.001258X2 + 0.04169X3 + 0.01843X4 - 0.01981X6 + 0.2200X8 ± 0.418, in the above equation, Y is the normal reference value of forced vital capacity of younger men (L); X1 is the altitude (m); X2 is the annual sunshine duration (h); X3 is the annual percentage of sunshine duration (%); X4 is the annual mean air temperature °C); X6 is the annual mean relative humidity (%); X8 is the annual mean wind speed (m/s); 0.418 is the value of the residual standard deviations. Conclusion If geographical values are obtained in a certain area, the normal reference value of forced vital capacity of younger men in this area can be reckoned by using the regression equation. Furthermore, according to the geographical factors, China can be divided into eight districts; Northeast China District, North China District, Shanxi-Shaanxi-Inner Mongolia District, Middle and lower reaches of the Changjiang River District, Southeast Chine District, Northwest China District and Southwest China District and Qinghai-Tibet Plateau District. [ABSTRACT FROM AUTHOR]