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Is GSN significant for hip BMD in female Caucasians?

ABSTRACT: Low bone mineral density (BMD) is a risk factor for osteoporosis. Osteoporosis is more prevalent in females than in males. So far, the pathophysiological mechanisms underlying osteoporosis are unclear. Peripheral blood monocytes (PBMs) are precursors of bone-resorbing osteoclasts. This study aims to identify PBM-expressed proteins (genes) influencing hip BMD in humans. We utilized three independent study cohorts (N=34, 29, 40), including premenopausal Caucasians with discordant hip BMD. We studied PBM proteome-wide protein expression profiles in cohort 1 and identified 57 differentially expressed proteins (DEPs) between low vs. high BMD subjects. One protein gelsolin (GSN), after validation by Western blotting, was subject to follow-up. We compared GSN mRNA level in PBM between low vs. high BMD subjects in cohorts 2 and 3. We genotyped SNPs across GSN in 2286 unrelated Caucasians (cohort 4) and 1627 Chinese (cohort 5) and tested their association with hip BMD in females and males, respectively. We discovered and validated that GSN protein expression level in PBM was down-regulated 3.0-fold in low vs. high BMD subjects (P<0.05). Down-regulation of GSN in PBM in low BMD subjects was also observed at mRNA level in both cohort 2 and cohort 3. We identified that SNP rs767770 was significantly associated with hip BMD in female Caucasians (P=0.0003) only. Integrating analyses of the datasets at DNA, RNA, and protein levels from female Caucasians substantiated that GSN is highly significant for hip BMD (P=0.0001). We conclude that GSN is a significant gene influencing hip BMD in female Caucasians.

SUBMITTER: Deng FY

PROVIDER: S-EPMC4127973 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Is GSN significant for hip BMD in female Caucasians?

Deng Fei-Yan FY Zhu Wei W Zeng Yong Y Zhang Ji-Gang JG Yu Na N Liu Yao-Zhong YZ Liu Yong-Jun YJ Tian Qing Q Deng Hong-Wen HW

Bone 20140304

Low bone mineral density (BMD) is a risk factor for osteoporosis. Osteoporosis is more prevalent in females than in males. So far, the pathophysiological mechanisms underlying osteoporosis are unclear. Peripheral blood monocytes (PBMs) are precursors of bone-resorbing osteoclasts. This study aims to identify PBM-expressed proteins (genes) influencing hip BMD in humans. We utilized three independent study cohorts (N=34, 29, 40), including premenopausal Caucasians with discordant hip BMD. We studi ...[more]

PMID: 24607942

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Project description:Serum proteomics analysis may lead to the discovery of novel osteoporosis biomarkers. The Osteoporotic Fractures in Men (MrOS) study comprises men ≥65 years old in the US who have had repeated BMD measures and have been followed for incident fracture. High-throughput quantitative proteomic analysis was performed on baseline fasting serum samples from non-Hispanic white men using a multidimensional approach coupling liquid chromatography, ion-mobility separation, and mass spectrometry (LC-IMS-MS). We followed the participants for a mean of 4.6 years for changes in femoral neck bone mineral density (BMD) and for incident hip fracture. Change in BMD was determined from mixed effects regression models taking age and weight into account. Participants were categorized into three groups: BMD maintenance (no decline; estimated change ≥0 g/cm2 , n = 453); expected loss (estimated change 0 to 1 SD below the estimated mean change, -0.034 g/cm2 for femoral neck, n = 1184); and accelerated loss (estimated change ≥1 SD below mean change, n = 237). Differential abundance values of 3946 peptides were summarized by meta-analysis to determine differential abundance of each of 339 corresponding proteins for accelerated BMD loss versus maintenance. Using this meta-analytic standardized fold change at cutoffs of ≥1.1 or ≤0.9 (p < 0.10), 20 proteins were associated with accelerated BMD loss. Associations of those 20 proteins with incident hip fracture were tested using Cox proportional hazards models with age and BMI adjustment in 2473 men. Five proteins were associated with incident hip fracture (HR between 1.29 and 1.41 per SD increase in estimated protein abundance). Some proteins have been previously associated with fracture risk (eg, CD14 and SHBG), whereas others have roles in cellular senescence and aging (B2MG and TIMP1) and complement activation and innate immunity (CO7, CO9, CFAD). These findings may inform development of biomarkers for future research in bone biology and fracture prediction. © 2017 American Society for Bone and Mineral Research.

Project description:Purpose To evaluate the effect of hip flexion and rotation on excursion of the gluteus medius (Gmed) and minimus (Gmin) myotendinous unit. Methods Seven hips from 4 cadaveric specimens (males, 68.5 ± 18.3 years old) were dissected to isolate the Gmed posterior and lateral insertions and the Gmin proximal and distal insertions. Sutures were placed from tendon insertions through origins created in the iliac fossa to simulate the myotendinous unit. A load of 10N was applied. Myotendinous excursion was measured at 10° hip extension and 0°, 45°, and 90° of hip flexion in neutral rotation, and from maximum internal and external rotation in 90° flexion. The amount of abduction and rotation was also measured at each flexion position with 20N applied to each tendon. Repeated-measures analysis of variance with Tukey post hoc was used for statistics. Results Gmed-lateral excursion ranged from 2.4 ± 0.4 mm in 10° of hip extension to 23.0 ± 1.5 mm in 90° of flexion (P < .001), and Gmed-posterior excursion ranged from 0.92 ± 0.5 mm in 10° of extension to 38.1 ± 1.1 mm in 90° of flexion (P < .001). Gmin excursion shortened with hip flexion from 4.2 ± 0.3 mm in 10° of extension to −0.2 ± 1.5 mm in 90° of flexion (Gmin-prox: P = .525, Gmin-distal: P < .001). At 90° flexion from maximum internal to maximum external rotation, Gmin-distal and proximal demonstrated a 92.6% and 51.3% increase in excursion, respectively (P < .001). Gmed-lateral and Gmed-posterior demonstrated 49.4% and 23.1% increase in excursion with external rotation, respectively (P < .001). Conclusions The Gmed myotendinous unit undergoes significant excursion with hip flexion, whereas both Gmed and Gmin had significant excursion with femoral external rotation in 90° flexion. Clinical Relevance It is important to understand whether active or passive hip flexion or rotation in the early postoperative period causes excessive strain to an abductor tendon repair. We found that consideration should be given to limit flexion after Gmed repair and external rotation after Gmed or Gmin repairs.

Project description:A suboptimal intrauterine environment has been postulated to have adverse long-term health effects, including an increased risk of osteoporosis. Because preeclampsia (PE) and to a lesser extent gestational hypertension (GH) are associated with impaired placental function, we postulated that these represent hitherto unrecognized risk factors for reduced bone mineral density (BMD) of the offspring. The objective of this study was to investigate if exposure to PE or GH in utero is associated with BMD of the offspring as measured in late adolescence. Mother-offspring pairs from the UK population-based cohort study, Avon Longitudinal Study of Parents and Children (ALSPAC), were investigated (n = 3088 with relevant data). Multivariable linear regression was used to examine associations between PE/GH and total body, spine, and total hip BMD at age 17 years. Of the 3088 mother-offspring pairs, 2% (n = 60) of the mothers fulfilled criteria for PE and 14% (n = 416) for GH. In confounder-adjusted analyses (ie, age of scan, gender, maternal factors, including BMI, offspring height, fat mass, and lean mass), PE was negatively associated with BMD at the hip (SD difference -0.30; 95%CI, -0.50 to -0.10). This association was not attenuated by further adjustment for gestational age and birth weight, which were hypothesized to be on the causal pathway. There was also weak evidence for a negative association between PE and total body BMD (SD difference -0.17; 95% CI, -0.36 to 0.02), whereas no relationship was evident at the spine (SD difference -0.11; 95% CI, -0.30 to 0.09). In contrast, a positive association of GH with offspring total body, hip, and spine BMD attenuated to the null with adjustment for confounders, in particular confounding via the maternal and offspring adiposity/size and the link between the two. Modest negative associations from exposure to PE, but not GH may represent a hitherto unrecognized risk factor for low BMD. Further exploration of the causal relationship of the in utero environment on subsequent offspring bone health is required.

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Is GSN significant for hip BMD in female Caucasians?

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Is GSN significant for hip BMD in female Caucasians?

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