Genetic factors influencing the pathogenesis of osteoporosis are still largely unknown. We employed genome-wide gene expression approach in order to discover novel genes involved in the pathogenesis of osteoporosis. To this end, primary cultures of osteoblasts isolated from osteoporotic and non-osteoporotic human bone tissue samples were prepared. One thousand six hundred six genes were found to be differentially expressed, indicating increased demand for protein synthesis and decreased cell proliferation rate in osteoblasts from osteoporotic tissue as compared to osteoblasts from non-osteoporotic tissue. At first, top four genes, based on the microarray data and potential role in bone metabolism, were further studied in bone tissue samples of 55 patients. PTN and COL15A1 were both downregulated in osteoporotic bone tissue (6.2- and 3.4-fold, respectively, both p ( 0.05), while IBSP and CXCL2 were both upregulated (5.7-fold, p ( 0.05, and 2.1-fold, p ) 0.05). Further biostatistical analysis of the microarray data by gene set enrichment analysis suggested oxidative stress may have an important part in the pathogenesis of osteoporosis. Thus, secondly, we tested it by an in vitro assay on human osteosarcoma cell line cells treated with hydrogen peroxide. After 72 h of treatment with 500 ?M hydrogen peroxide, the upregulation of thesame genes involved in the response to oxidative stress as on the microarrays was observed: MT1G (metallothionein 1G, 22.1-fold, p ( 0.05), TXNRD1 (thioredoxin reductase 1, 3.7-fold, p ( 0.05), AOX1 (aldehyde oxidase 1, 24.5-fold, p ( 0.05) and GSR (glutathione reductase, 4.7-fold, p ( 0.05). Our results present a novel list of genes and metabolic pathways that may be associated with the pathogenesis of osteoporosis. PTN, CXCL2, COL15A1, IBSP, AOX1, MT1G, GSR and TXNRD1 are candidate genes for further studies in the assessment of the genetic susceptibility to osteoporosis. In addition, differences in protein synthesis, cell proliferation rate and response to oxidative stress may also be involved in the pathogenesis of osteoporosis.
COBISS.SI-ID: 2678385
Objective: Oxidative stress participates in decreasing bone formation and stimulating bone resorption. Furthermore, antioxidant enzymes have been observed to have low protective activity in women with osteoporosis. The aim of the present study was to examine any association of selected gene polymorphisms of the glutathione S-reductase (GSR), superoxide dismutase (SOD1and SOD2), and catalase (CAT) genes, alone or in combination, with the bone mineral density (BMD) values of femoral neck (fn), lumbar spine (ls), andtotal hip (th) in Slovenian postmenopausal women. Methods: The gene polymorphisms of CAT, GSR, SOD1, and SOD2 genes in 468 postmenopausal women were analyzed using restriction fragment length polymorphism and a fluorescent5'-exonuclease genotyping method. BMD_fn, BMD_ls, and BMD_th were measured using dual-energy x-ray absorptiometry. Moreover, univariate statistic analysis and two-way analysis of variance for interaction testing were performed. Results: A significant association of BMD_th values (P = 0.027) was found in genotype subgroups of 423-287G)A GSR polymorphism located in the third intron among postmenopausal women. Furthermore, women with at least one G allele showed significantly higher levels of BMD_fn (P = 0.044), BMD_th (P = 0.009), and BMD_ls (P = 0.043) than those that are AA homozygotes.Interestingly, the 423-287G)A_GSR*1154-393T)A_GSR combination was significantly associated with BMD_fn (P = 0.013) and BMD_th (P = 0.002) in postmenopausal women. Conclusions: The results of our study demonstrate for the first time that antioxidant enzyme GSR gene polymorphisms are significantly associated with BMD, suggesting that the A allele of 423-287G)A GSR polymorphism could contribute to decreased BMD values in postmenopausal women.
COBISS.SI-ID: 3156593
Bone mineral density (BMD) is the most widely used predictor of fracture risk.We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 1 17 genome-wide association studies and 32,961 1 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 1 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P ( 5 Ž 1 10Ž8). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P ( 5 Ž 1 10Ž4, Bonferroni corrected), of which six reached P ( 5 Ž 1 10Ž8, including at 1 18p1111.21 (FAM210A), 7q21.3 (SLC25A13), 11 11 11q13.2 (LRP5), 4q22.1 1 (MEPE), 2p16.2 (SPTBN1) and 1 10q21.1 1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.
COBISS.SI-ID: 3233137
Objective: The effect of metformin on weight reduction in polycystic ovary syndrome (PCOS) is often unsatisfactory.In this study, we investigated the potential add-on effect of treatment with the glucagonlike peptide1 receptor agonistliraglutide on weight loss in obese nondiabetic women with PCOS who had lost !5% body weight during pretreatmentwith metformin.Methods: A total of 40 obese women with PCOS, who had been pretreated with metformin for at least 6 months,participated in a 12week open label, prospective study. They were randomized to one of three treatment arms: metformin(MET) arm 1000 mg BID, liraglutide (LIRA) arm 1.2 mg QD s.c., or combined MET 1000 mg BID and LIRA (COMBI) 1.2 mg QDs.c. Lifestyle intervention was not actively promoted. The primary outcome was change in body weight.Results: Thirty six patients (aged 31.3G7.1 years, BMI 37.1G4.6 kg/m2) completed the study: 14 on MET, 11 on LIRA, and 11 oncombined treatment. COMBI therapy was superior to LIRA and MET monotherapy in reducing weight, BMI, and waistcircumference. Subjects treated with COMBI lost on average 6.5G2.8 kg compared with a 3.8G3.7 kg loss in the LIRA groupand a 1.2G1.4 kg loss in the MET group (P!0.001). The extent of weight loss was stratified: a total of 38% of subjects werehigh responders who lostR5% body weight, 22% of them in the COMBI arm compared with 16 and 0% in the LIRA and METarm respectively. BMI decreased by 2.4G1.0 in the COMBI arm compared with 1.3G1.3 in LIRA and 0.5G0.5 in the MET arm(P!0.001). Waist circumference also decreased by 5.5G3.8 cm in the COMBI arm compared with 3.2G2.9 cm in LIRAand 1.6G2.9 cm in the MET arm (PZ0.029). Subjects treated with liraglutide experienced more nausea than those treatedwith metformin, but severity of nausea decreased over time and did not correlate with weight loss.Conclusions: Shortterm combined treatment with liraglutide and metformin was associated with significant weight loss anddecrease in waist circumference in obese women with PCOS who had previously been poor responders regarding weightreduction on metformin
COBISS.SI-ID: 1275820
CONTEXT: Phosphodiesterase (PDE) enzymes, including members of PDE4, have been investigated in the regulation of endocrine and reproductive functions of ovaries. In addition, selective inhibition of PDE4 enzyme has recently been implicated in the regulation of metabolism with positive effects on glucose homeostasis and weight reduction. OBJECTIVE: The aim of this study was to evaluate whether the PDE4 inhibitor roflumilast affects body weight and hormonal and metabolic status in obese women with polycystic ovary syndrome (PCOS). Design/Participants/Main Outcome Measures: A 12-week prospective randomized open-label study was conducted with 36 obese women with PCOS diagnosed by the National Eunice Kennedy Shriver Institute of Child Health and Human Development criteria that had been pretreated with metformin (MET). They were randomized to MET 1000 mg twice a day or combined treatment (COM) with MET 1000 mg twice a day and roflumilast 500 μg every day. The primary outcome was change in anthropometric measures of obesity. RESULTS: Thirty-one patients (aged 33.8 ± 7.4 y, twice a day 36.4 ± 5.1 kg/m(2), mean ± SD) completed the study: 16 on MET and 15 on COM. Subjects treated with COM lost on average 4.2 ± 2.8 kg compared with a 0.9 ± 2.5 kg weight gain in the MET group (P = .025). Body mass index decreased for 1.6 ± 1.1 kg/m(2) in COM arm compared with increase for 0.9 ± 2.4 kg/m(2) in the MET arm (P = .046). Visceral adipose tissue area as assessed by dual-energy x-ray absorptiometry decreased from 136.7 ± 37.8 to 121.2 ± 36.2 cm(2) in the COM arm compared with an increase from 155.3 ± 61.9 to 166.7 ± 67.2 cm(2) in the MET arm (P = .02). From baseline to study end, both treatment interventions resulted in a significant reduction of androstenedione (P = .013), free T (P = .002), and homeostasis model assessment for insulin resistance score (P = .027) and a significant increase in SHBG (P = .024), although the between-treatment differences of the changes have not been statistically significant yet.
COBISS.SI-ID: 1796780