Jian-min Liu

The influence of Lys3Asn polymorphism in the osteoprotegerin gene on bone mineral density in Chinese postmenopausal women

The objective was to identify single nucleotide polymorphisms (SNPs) in exons of the osteoprotegerin gene and to analyze the relationship between the SNPs and bone mineral density in postmenopausal women. We used polymerase chain reaction (PCR) and direct sequencing methods to identify SNPs and genotypes in 205 postmenopausal women. BMD at the lumbar spine (L2–4) and femoral neck (FN) were measured by dual-energy X-ray absorptiometry (DEXA). Serum osteocalcin (OC), osteoprotegerin (OPG), receptor activator of nuclear factor κB ligand (RANKL) and urinary N-telopeptide of type I collagen (NTx) were also measured. In exon 1 of the OPG gene, we found the Lys3Asn SNP. In 205 postmenopausal women, the Asn-allele frequency was 26.0%, and the distribution of Lys3Asn genotypes was Lys-Lys 56.6%, Lys-Asn 34.6% and Asn-Asn 8.8%, respectively. BMD at the lumbar spine (L2–4) of the Asn-Asn genotype was significantly higher (9.5–12.6%) than Lys-Asn and Lys-Lys genotypes ( P =0.012), with evidence for an allele dose effect ( P =0.008). Results remained similar after adjustment for age and body mass index. The Lys3Asn polymorphism of the OPG gene alone accounted for 7.7% of the variance of the L2–4 BMD in a multiple regression model. Logistic regression analysis revealed that the OPG genotype Lys-Lys had a 2.7 times (95% CI: 0.83–9.11) greater risk for osteopenia/osteoporosis than the Asn-Asn genotype. The Lys3Asn polymorphism in the OPG gene is associated with L2–4 BMD in postmenopausal women. The Lys-allele is associated with lower BMD and an increased risk for osteoporosis.

Relationship between body composition and bone mineral density in healthy young and premenopausal Chinese women

This study investigated the relative contribution of fat mass and lean mass to bone mineral density (BMD) in young and premenopausal healthy Chinese women. The study was performed in 282 young and premenopausal healthy women with regular menstrual cycles. The BMD at lumbar spine (L2–L4), total hip and total body, together with fat mass and lean mass were assessed by dual-energy X-ray absorptiometry (DXA); body height, weight, waist and hip circumference were also measured, and body mass index (BMI) and waist-hip ratio were calculated. Fat mass was a major determinant for BMI, BMI and lean mass were positively related to L2–L4, total hip and total body bone density (P<0.001 for all), lean mass was the only independent factor contributing to BMD at L2–L4 (standardized coefficient β=0.282, P<0.001), total hip (β=0.336, P<0.001) and total body (β=0.361, P<0.001) in multiple stepwise regression analysis. The correlation between BMI and BMD was improved after adjustment for fat mass, while decreased or even lost when lean mass was adjusted. These data suggested that in the Chinese population, lean mass is an important factor determining BMD in young and premenopausal women.

Analysis of Recently Identified Osteoporosis Susceptibility Genes in Han Chinese Women

BACKGROUND In Europeans and populations of European origin, several osteoporosis susceptibility genes, including ZBTB40, RANK, RANKL, OPG, MHC, and ESR1, were recently identified. However, none of these has been fully investigated in Han Chinese populations. OBJECTIVE AND DESIGN In this relatively large cross-sectional sample of 1012 Han Chinese women, 21 single-nucleotide polymorphisms (SNPs) within 11 candidate genes that were newly identified in Europeans were tested, and their associations with bone mineral densities (BMDs) and osteoporotic fracture were investigated. RESULTS A total of 21 SNPs were genotyped. Five SNPs in four genes [ZBTB40 (rs7524102, rs6696981), ESR1 (rs9479055), OPG (rs6469804), and RANK (rs3018362)] were found to be associated with lumbar spine BMD. Seven SNPs in five genes [ZBTB40 (rs7524102, rs6696981), OPG (rs6993813, rs6469804), RANK (rs3018362), LRP5 (rs3736228), and SOST (rs1513670)] were found to be associated with total hip BMD. SPTBN1 (rs11898505) and SOST (rs1107748) were associated with osteoporotic fracture. A significant gene-gene interaction for osteoporotic fracture involving rs1107748 in SOST and rs6469804 in OPG gene was identified from generalized multifactor dimensionality reduction analysis. CONCLUSIONS Our study provides an independent replication of the associations between several SNPs in ZBTB40, ESR1, OPG, RANK, LRP5, and SOST with lumbar spine and/or total hip BMDs in a large sample of Han Chinese women. The results of this study further support the significant associations found between osteoporotic fracture and SNPs in SPTBN1 and SOST. Our results suggest that these variants represent osteoporosis susceptibility genes in both Han Chinese and European populations.

Osteoporotic fractures in Asia: risk factors and strategies for prevention.

J.-M. Liu · G. Ning (*) · J.-L. Chen Department of Endocrine and Metabolic Diseases, Rui-jin Hospital; Shanghai Jiao-tong University Medical School; Shanghai Clinical Center for Endocrine and Metabolic Diseases; Endocrine and Metabolic Division, E-Institute of Shanghai Universities (EISU), 197 Shanghai Rui-jin Er Road, Shanghai 200025, China Tel. +86-21-6437-0045, ext. 665345; Fax +86-21-6437-3514 e-mail: guangning@medmail.com.cn Jian-min Liu · Guang Ning · Jia-lun Chen

NMDA enhances stretching-induced differentiation of osteobalsts through the ERK1/2 signaling pathway

Activation of the excitatory neurotransmitter N-methyl-d-aspartate (NMDA) and stretching both increase Ca(2+) influx in osteoblastic cells. We postulated that NMDA would enhance the osteoblastic cells response to stretching. The goal of this study was to investigate, in the presence of the neurotransmitter NMDA, the effect of mechanical loading on osteoblasts stage of differentiation and the mitogen-activated protein kinase (MAPK) signaling pathway associated with it. Rat primary osteoblastic cells were subjected to cyclic, equibiaxial stretch for 48 h in the presence or absence of NMDA. Pretreatment with 0.5 mM NMDA significantly enhanced the stretching magnitude-dependent increase in osteogenesis markers. MK801, an antagonist of NMDA receptors, abolished those responses. To further study the mechanism of this response, osteoblastic cells were stretched for 5, 15, or 60 min in the absence of NMDA. Cyclic stretch induced a rapid increase in extracellular signal-regulated kinase ERK1/2 phosphorylation with the peak at 15 min, but no changes were noted in p38 and JNK pathway signaling. NMDA could enhance ERK1/2 phosphorylation stimulated by stretching. U0126, an inhibitor of ERK1/2, blocked the increase in osteogenesis markers. In conclusion, the current study demonstrates that there is a synergistic effect between mechanical stimulation and NMDA in osteoblasts. ERK1/2 signaling may be the common pathway in the increased response to stretching in the presence of NMDA in osteoblastic cells.