绝经后妇女血清激素受体共激活因子3与骨密度、骨转换水平的相关性

doi:10.3969/j.issn.2095-4344.2017.32.002

中国组织工程研究 ›› 2017, Vol. 21 ›› Issue (32): 5091-5096.doi: 10.3969/j.issn.2095-4344.2017.32.002

• 骨组织构建 bone tissue construction • 上一篇下一篇

绝经后妇女血清激素受体共激活因子3与骨密度、骨转换水平的相关性

展磊1，魏秋实2

(1广州市天河区石牌桥社区卫生服务中心，广东省广州市 510660；2广州中医药大学第一附属医院骨科，广东省广州市 510405)

收稿日期:2017-07-25 出版日期:2017-11-18 发布日期:2017-11-15
通讯作者: 魏秋实，博士，主治医师，硕士生导师，广州中医药大学第一附属医院骨科，广东省广州市 510407
作者简介:展磊，男，1980年生，山东省青岛市人，汉族，2008年广州中医药大学毕业，博士，主治医师，从事中医药防治社区慢性病的研究。
基金资助:
国家自然科学基金项目(81302994，81473697)

Implication of serum steroid receptor coactivator-3
level for lumbar bone mineral density and bone turnover in postmenopausal women

Zhan Lei1, Wei Qiu-shi 2

(1Shipai Street Community Health Center of Tianhe District of Guangzhou, Guangzhou 510660, Guangdong Province, China; 2Department of Orthopedics, First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405, Guangdong Province, China)

Received:2017-07-25 Online:2017-11-18 Published:2017-11-15
Contact: Wei Qiu-shi, M.D., Attending physician, Master’s supervisor, Department of Orthopedics, First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405, Guangdong Province, China
About author:Zhan Lei, M.D., Attending physician, Shipai Street Community Health Center of Tianhe District of Guangzhou, Guangzhou 510660, Guangdong Province, China
Supported by:
the National Natural Science Foundation of China, No. 81302994 and 81473697

摘要/Abstract

摘要：

文章快速阅读：

文题释义：
激素受体共激活因子：是一类可以辅助多种转录因子并在转录水平上调节多种基因的表达的辅激活因子，在不同的组织细胞中表现出一定的特异性及复杂性，主要包括激素受体共激活因子1、激素受体共激活因子2和激素受体共激活因子3。
激素受体共激活因子3：是类固醇激素核受体超家族成员，它通过与核受体和其它转录因子相互作用来调控转录激活功能，在维护老年人椎体骨量方面可能发挥一定的作用。骨转换标志物包括两类：去除旧骨(吸收)和产生新骨(形成)。Ⅰ型原胶原N-端前肽和β-胶原特殊序列分别是代表骨形成和骨吸收的标记物，在临床上可用于评价骨代谢的状态。

摘要
背景：激素受体共激活因子3属于类固醇激素核受体超家族成员，可通过调节雌激素受体活性促进人成骨细胞增殖和分化。研究发现高加索男性激素受体共激活因子3等位基因突变与腰椎骨密度的变化密切相关。而在绝经后妇女中激素受体共激活因子3是否与骨密度相关尚不清楚。
目的：检测绝经后妇女血清激素受体共激活因子3水平及其与骨密度和骨转换水平的关系。
方法：检测55名绝经后妇女和35例健康体检者的血清中激素受体共激活因子3、25羟维生素D、骨钙素和骨转换标志物Ⅰ型原胶原N-端前肽、β-胶原特殊序列水平，同时以双能X射线骨密度仪测量L1-4及股骨颈骨密度。
结果与结论：绝经后骨质疏松组血清激素受体共激活因子3水平明显低于健康对照组，血清激素受体共激活因子3水平与腰椎骨密度呈正相关，与Ⅰ型原胶原N-端前肽和骨钙素水平呈负相关。说明低血清激素受体共激活因子3水平可能参与绝经型骨质疏松症的病理过程，且可能调控骨转换水平。

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程
orcid: 0000-0003-2834-3913(Zhan Lei)

关键词: 组织构建, 骨组织工程, 激素受体共激活因子3, 绝经后妇女, 骨密度, 骨代谢, 骨转换标记物, 骨质疏松症, 国家自然科学基金

Abstract:

BACKGROUND: Steroid receptor coactivator-3 (SRC-3) is a member of the steroid receptor coactivator family, and it can promote proliferation and differentiation in human osteoblasts by modulating estrogen receptor activity. Previous studies have reported that allelic variation at the SRC-3 locus is significantly positively correlated with the lumbar bone mineral density in Caucasian men, but the relationship between SRC-3 and bone metabolism in postmenopausal women remains unknown.
OBJECTIVE: To investigate the level of serum SRC-3 in postmenopausal women and its association with bone mineral density and bone turnover markers.
METHODS: Fifty-five women with postmenopausal osteoporosis and 35 healthy postmenopausal women were recruited, and their serum levels of SRC-3, 25-hydroxyvitamin D, osteocalcin and procollagen I N-terminal peptide, beta C-terminal telopeptide of type I collagen were detected. The bone mineral density of L1-4 vertebrae and femoral neck were measured by dual-energy X-ray absorptiometry.
RESULTS AND CONCLUSION: Serum SRC-3 level in postmenopausal women with osteoporosis was remarkably lower than that in healthy individuals. In addition, the serum SRC-3 level was positively correlated with lumbar bone mineral density, and negatively correlated with procollagen I N-terminal peptide and osteocalcin in postmenopausal women with osteoporosis. These results indicate that low serum SRC-3 level may be involved in the pathogenesis of postmenopausal osteoporosis and play a pivotal role in bone turnover.

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

Key words: Osteoporosis, Postmenopausal, Bone Density, Tissue Engineering

中图分类号:

R318

展磊，魏秋实. 绝经后妇女血清激素受体共激活因子3与骨密度、骨转换水平的相关性[J]. 中国组织工程研究, 2017, 21(32): 5091-5096.

Zhan Lei1, Wei Qiu-shi 2. Implication of serum steroid receptor coactivator-3
level for lumbar bone mineral density and bone turnover in postmenopausal women[J]. Chinese Journal of Tissue Engineering Research, 2017, 21(32): 5091-5096.

图/表（结果） 3

Clinical data of the participants

Ninety postmenopausal women with physiological menopause were included in the study. According to the World Health Organization (WHO) criteria, 55 (61.1%) of the subjects were diagnosed as having osteoporosis and 35 (38.9%) had normal BMD values.

The anthropometric, laboratory data, and BMD in the normal PMW and PMW with osteoporosis are listed in

Table 1. There were no significant differences in the age, body mass, height, serum, and osteocalcin between two groups. Body mass index was lower in PMW with osteoporosis than that in normal PMW. Serum PINP and β-CTX levels were higher in PMW with osteoporosis than those in normal PMW. The difference in SRC-3 level between two groups was significant (P < 0.001).

Relationship of serum SRC-3 level with bon-related variables

The relationship between serum SRC-3 level and bone-related variables in PMW with osteoporosis and normal PMW was detected. As shown in Table 2, serum SRC-3 level was positively associated with lumbar BMD and lumbar BMD T-score (r=0.500, P < 0.001; r=0.412, P =0.002) and negatively correlated with serum PINP and osteocalcin levels (r=-0.369, P < 0.006; r=-0.515, P < 0.001) in PMW with osteoporosis. No association between serum SRC-3 and the remaining variables was found in PMW with osteoporosis. Serum SRC-3 level was negatively correlated with age (r=-0.443, P=0.008) in normal PMW. No correlation between serum SRC-3 and

other parameters was observed in normal PMW.

Multiple regression analyses with serum SRC-3 level as a dependent variable

A multiple regression analysis was performed to determine the predictors of SRC-3 after adjustment for the confounding variables. SRC-3 was designated as the dependent variable, whereas age, body mass, height, body mass index, serum 25-hydroxyvitamin D, PINP, β-CTX, osteocalcin, lumbar BMD and femoral neck BMD were included as the independent variables. In this assay, osteocalcin and lumbar BMD were independent predictors of serum SRC-3 level in PMW with osteoporosis, after adjustment for age, body mass, height, body mass index, serum 25-hydroxyvitamin D, PINP, β-CTX, and femoral neck BMD (Table 3). Figure1 shows the correlation of serum SRC-3 levels with lumbar BMD, PINP, and osteocalcin, respectively.

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引言

Steroid receptor coactivator-3 (SRC-3), also known as nuclear receptor coactivator-3, was first identified in human breast cancer cells and amplified in estrogen receptor (ER)-positive breast cancer cell lines^[1]. SRC-3 is an important ERα co-activator. SRC-3 silencing can inhibit cell proliferation and survival stimulated by estrogen in ERα-positive human breast cancer cells^[2-4]. Thus, SRC-3 plays a tumor-promoting role and might be an effective therapeutic target for ER-positive breast cancers.

Estrogen plays a pivotal role in maintaining bone mineral density (BMD) in estrogen-deficient postmenopausal women (PMW)^[5]. Seals et al.^[6] reported that ERα expression was lower in vascular endothelial cells obtained from PMW. Ikeda et al.^[7] showed that osteoblast-targeted overexpression of ERα increased the BMD in mice. In addition, ERα gene polymorphism is positively associated with BMD in PMW^[8]. Therefore, ERα is a pivotal factor for maintaining the BMD in PMW.

Recently, SRC-3 has been shown to specifically interact with ERα to promote proliferation and differentiation of MG-63 cells, and protecte against cell death^[9]. In aged Caucasian men, allelic variation at the SRC-3 locus was significantly positively correlated with lumbar BMD^[10], indicating that it might be an important regulatory factor in bone metabolism. That is to say, SRC-3 not only can regulate ERα-dependent proliferation and differentiation in human osteoblasts, but also may influence ERα-dependent bone formation in PMW. But there is a lack of knowledge about the relationship between serum SRC-3 level and BMD in PMW. Therefore, in this study, we attempted to evaluate whether serum SRC-3 level is associated with BMD in PMW.

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

材料方法

MATERIALS AND METHODS

Design

A cross-sectional design.

Time and setting

This study was imposed at the First Affiliated Hospital of Guangzhou University of Chinese Medicine from June 2012 to September 2013.

Subjects

Fifty-five PMW, mean age of (55.85±9.78) years, with osteoporosis were recruited in osteoporosis specialist out-patient; 35 healthy women, mean age of (55.14±5.91) years, who participated in the annual health examination in the medical examination center at the First Affiliated Hospital of Guangzhou University of Chinese Medicine were recruited. Osteoporosis and osteopenia were diagnosed according to the World Health Organization criteria^[11]. Age, height, body mass, and body mass index were recorded. The study protocol was approved by the Ethical Committee of the First Affiliated Hospital of Guangzhou University of Chinese Medicine, and written informed consent was obtained from each subject prior to the participation in the trial.

The inclusion criteria were: (1) BMD of L₁_-₄ and femoral neck performed at our institution with a standardized protocol; (2) patients receiving no systemic treatment.

The exclusion criteria: (1) diseases affecting bone metabolism including diabetes mellitus, hyperparathyroidism, thyroid disorders, liver and kidney diseases, cancer, rheumatoid arthritis, or other metabolic diseases; (2) having taken medicine (such as bisphosphonate, diuretics, adrenal and thyroid drugs, corticosteroids, vitamin D and/or calcium supplements) within the past 12 months.

Methods

Serum collection and analysis

All fasting blood samples were taken from the antecubital vein in the morning in order to determine the levels of serum 25-hydroxyvitamin D, procollagen I N-terminal peptide (PINP), and beta C-telopeptide of collagen (β-CTX) at the department of Clinical Biochemistry at the First Affiliated Hospital of Guangzhou University of Chinese Medicine. The levels of serum 25-hydroxyvitamin D, PINP, and β-CTX were measured by electrochemiluminescence immunoassay (Cobase 411, Roche Diagnostics, Mannheim, Germany). The intra-assay coefficients of variation for 25-hydroxyvitamin D were 7.5% at a level of 7.16 ng/mL, 5.0% at a level of 15.6 ng/mL, 3.0% at a level of 28.7 ng/mL, and 1.7% at a level of 67.9 ng/mL. The inter-assay coefficients of variation for 25-hydroxyvitamin D were 13.6% at a level of 7.16 ng/mL, 8.8% at a level of 15.6 ng/mL, 5.5% at a level of 28.7 ng/mL, and 2.2% at a level of 67.9 ng/mL. The lower limit of detection of 25-hydroxyvitamin D was < 3 ng/mL (< 7.5 nmol/L), and the higher limit of detection of 25-hydroxyvitamin D was < 70 ng/mL (< 175 nmol/L). The intra- and inter-assay coefficients of variation were 6.5% and 6.1% for PINP and 4.3% and 5.8% for β-CTX, respectively. Blood samples (4 mL) were collected in drying tubes. After agglutination, the blood was centrifuged at room temperature for 10 minutes at 1 000×g. The serum was divided into 0.5 mL aliquots and immediately stored at -80 ℃ until further use.

Serum SRC-3 and osteocalcin levels were measured by ELISA (CUSABIO BIOTECH, Wuhan, China). The average sensitivity of SRC-3 and osteocalcin kit was 4.68 pg/mL and 0.078 ng/mL, respectively, both of which had the same intraassay (< 8%) and interassay (< 10%) coefficients of variation.

BMD examination

BMD of L₁_-₄ and femoral neck was determined by dual energy X-ray absorptiometry (DEXA; Lunar Prodigy, GE Medical Systems, Madison, USA). To eliminate operator differences, the same operator tested all the subjects during the study. The coefficients of variation for the lumbar BMD and femoral neck BMD were 0.60% and 0.89%, respectively.

Main outcome measures

Serum 25-hydroxyvitamin D, PINP, and β-CTX levels were measured by electrochemiluminescence immunoassay, and serum SRC-3 and osteocalcin levels were measured by ELISA. L_1–4 and femoral neck area BMD were determined using dual energy X-ray absorptiometry. The relationships between SRC-3 and BMD, serum 25-hydroxyvitamin D, PINP, and β-CTX, as well as osteocalcin level were investigated.

Statistical analysis

Normally distributed data are expressed as the mean±SD. Data that were not normally distributed are shown as medians and interquartile ranges. P < 0.05 was considered statistically significant. All analyses were performed using SPSS 13.0 (SPSS Inc., Chicago, IL, USA). Normal distribution of the data was ascertained by the Shapiro-Wilk test. The differences between groups were compared by independent-samples t test. Comparisons between groups were made using Mann-Whitney U test for two groups when the variances were not normal distribution. Pearson correlation analyses were used when bone related parameters followed a normal distribution. Spearman’s rank correlation test was performed to determine the relationship between pairs of bone related variables which did not follow a normal distribution. Multiple regression analysis was used to determine the influence of one independent variable on serum SRC-3 level after correcting for others.

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

讨论

Three homologous members (SRC-1, SRC-2, and SRC-3)of p160 SRC family are the important regulatory factors for breast cancer cell proliferation and ERα transcriptional activity^[12-14]. Moreover, each SRC family member is indicated to regulate the estrogen-dependent expression of ERα target genes^[15]. Previous studies examined bone phenotypes of SRC-1 or SRC-2 knockout under normal condition, followed by ovariectomy and with estrogen replacement therapy^[16]. Some studies showed that cancellous BMD decreased in SRC-1 knockout deletion of SRC-1 impaired estrogen action in cancellous^[17-19]. Accordingly, Mödder et al. ^[20] showed that SRC-2 knockout female mice led to increased trabecular bone mass and skeletal resistance to PPARγ predominantly. Jeong et al. ^[21] demonstrated that SRC-2 regulated uterine function probably by modulating the expression of ER. Because SRC-3 appears to be the preferred coactivator for ERα in breast cancer cells and human osteoblasts, we anticipated that SRC-3 could regulate the bone metabolism.

Numerous studies have provided clues on the relationship between SRC-3 and bone metabolism. Wang et al. ^[9]reported that SRC-3 was expressed by human osteoblasts and that estrone-rhein hybrid compounds might promote activation of ERα-dependent classic estrogen response element through increasing SRC-3 expression. Some studies demonstrated the correlation between allelic variation at the SRC-3 locus and BMD in human. Sheu et al. ^[10] showed that SRC-3 gene was significantly correlated with lumbar BMD in senile Caucasian men. Patel et al. ^[22] indicated that SRC-3 alleles were associated with calcaneal ultrasound in young women. This cross-sectional study confirmed that SRC-3 was detectable in PMW serum and demonstrated that PMW with osteoporosis had lower SRC-3 serum level than healthy PMW. We also found that serum PINP and β-CTX levels, which determine the bone formation and resorption, are higher in osteoporotic PMW. It showed that bone resorption was increased in PMW with osteoporosis, bone formation appeared compensative increase accompanying excessive bone resorption. Additionally, we observed a positive association between serum PINP and β-CTX levels (r=0.811, P < 0.001) in PMW with osteoporosis. These results might be direct reflection of high bone conversion status and the balance compensative mechanism between bone formation and resorption in postmenopausal women. Interestingly, we found body mass index was lower in PMW with osteoporosis. This seems to be rational, since body mass index was considered to be a significant and positive predictor of BMD at the lumbar spine and femoral neck^[23-29].

Consistent with the study on Caucasian men^[10], an interesting observation in the present study showed that serum SRC-3 level was significantly positively associated with lumbar BMD in PMW with osteoporosis. The pattern was unchanged in a multiple regression model. This might partly explain why serum SRC-3 level was lower in PMW with osteoporosis. We also found a negative correlation of serum SRC-3 level with PINP and osteocalcin in PMW with osteoporosis. Correlation between the serum SRC-3 and PINP levels was not persisted after adjustment for age, body mass, height, body mass index, serum 25-hydroxyvitamin D, β-CTX, lumbar BMD, and femoral head BMD. Osteocalcin is a marker of bone formation. Our study showed that osteocalcin level did not differ significantly between osteoporotic and healthy PMW. However, a significant negative association of serum SRC-3 level with osteocalcin in osteoporotic PMW was found. The pattern was significant in a multiple regression model. Moreover, a negative correlation between serum osteocalcin level and lumbar BMD (r=-0.344, P=0.010) was observed in osteoporotic PMW, which was in agreement with previous report by Vs et al.^[30]_.These findings support SRC-3 might be a protective factor for lumbar BMD in PMW with osteoporosis. However, it is difficult to explain the negative association of serum SRC-3 level with PINP and osteocalcin. For the contradictory phenomenon, the rational explaination would be that the positive role of SRC-3 on bone metabolism is decreased with bone turnover level increasing in PMW. This explaination was supported by our data that serum SRC-3 level negatively associated with age in normal PMW. Notably, no correlation between serum SRC-3 level and age was found in osteoporotic PMW, which might be a compensatory manner.

There was no association between SRC-3 and the remaining variables in healthy PMW. We expected that the function of SRC-3 on bone metabolism was not established in healthy PMW.

Our data indicate that PMW with osteoporosis has a decreased serum level of SRC-3 compared with normal PMW. Besides, there is a obviously positive association of serum SRC-3 level with lumbar BMD, and negative correlation with PINP and osteocalcin in PMW with osteoporosis. Therefore, SRC-3 may be involved in the pathogenesis of postmenopausal osteoporosis and play a pivotal role in bone turnover. This is a cross-sectional design; hence, no sufficient causality could be demonstrated for the relationship between serum SRC-3 level and other variables. Further studies are needed to explore the underlying mechanisms of SRC-3 regulating bone metabolism in osteoporotic PMW.

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

绝经后妇女血清激素受体共激活因子3与骨密度、骨转换水平的相关性

Implication of serum steroid receptor coactivator-3
level for lumbar bone mineral density and bone turnover in postmenopausal women

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绝经后妇女血清激素受体共激活因子3与骨密度、骨转换水平的相关性

Implication of serum steroid receptor coactivator-3 level for lumbar bone mineral density and bone turnover in postmenopausal women

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引用本文

使用本文

Implication of serum steroid receptor coactivator-3
level for lumbar bone mineral density and bone turnover in postmenopausal women