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      Follicle-Stimulating Hormone Increases the Risk of Postmenopausal Osteoporosis by Stimulating Osteoclast Differentiation

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          Abstract

          Objective

          The objectives of this study were to observe the changes in follicle-stimulating hormone (FSH) and bone mineral density (BMD) in postmenopausal women, to research the relationship between FSH and postmenopausal osteoporosis, and to observe the effects of FSH on osteoclast differentiation in RAW264.7 cells.

          Methods

          We analyzed 248 postmenopausal women with normal bone metabolism. A radioimmunoassay (RIA) was used to detect serum FSH, luteinizing hormone (LH), and estradiol (E 2). Dual-energy X-ray absorptiometry was used to measure forearm BMD. Then, we analyzed the age-related changes in serum FSH, LH and E 2. Additionally, FSH serum concentrations were compared between a group of postmenopausal women with osteoporosis and a control group. Osteoclasts were induced from RAW264.7 cells in vitro by receptor activator of nuclear factor kappa B ligand (RANKL), and these cells were treated with 0, 5, 10, and 20 ng/ml FSH. After the osteoclasts matured, tartrate-resistant acid phosphatase (TRAP) staining was used to identify osteoclasts, and the mRNA expression levels of genes involved in osteoclastic phenotypes and function, such as receptor activator of NF-κB ( Rank), Trap, matrix metalloproteinase-9 ( Mmp-9) and Cathepsin K, were detected in different groups using real-time PCR (polymerase chain reaction).

          Results

          1. FSH serum concentrations in postmenopausal women with osteoporosis increased notably compared with the control group. 2. RANKL induced RAW264.7 cell differentiation into mature osteoclasts in vitro. 3. FSH increased mRNA expression of genes involved in osteoclastic phenotypes and function, such as Rank, Trap, Mmp-9 and Cathepsin K, in a dose-dependent manner.

          Conclusions

          The circulating concentration of FSH may play an important role in the acceleration of bone loss in postmenopausal women. FSH increases osteoclastogenesis in vitro.

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          Most cited references27

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          Hormone predictors of bone mineral density changes during the menopausal transition.

          OBJECTIVE AND CONTEXT: Our objective was to examine predictability of reproductive hormone concentrations for bone mineral density (BMD) loss during the menopausal transition. We conducted a longitudinal (five annual examinations), multiple-site (n = 5) cohort study, the Study of Women's Health Across the Nation (SWAN). Participants included, at baseline, 2311 premenopausal or early perimenopausal African-American, Caucasian, Chinese, and Japanese women. We assessed annual dual-energy x-ray absorptiometry lumbar spine and total hip BMD measures, with endogenous estradiol (E2), FSH, androgens, and self-reported menstrual bleeding patterns. Over the 4-yr period, lumbar spine BMD loss was 5.6% in natural postmenopause, 3.9% in surgical postmenopause, or 3.2% in late perimenopause. Baseline FSH concentrations, subsequent FSH levels, and their interaction predicted 4-yr BMD loss. If baseline FSH was less than 25 mIU/ml, higher follow-up FSH (>70 mIU/ml) predicted a 4-yr spine BMD loss of -0.05 g/cm(2). If baseline FSH values were more than 35-45 mIU/ml, lower follow-up FSH (i.e. 40-50 mIU/ml) predicted a -0.05 g/cm(2) 4-yr spine BMD loss. Charts show amounts of predicted BMD losses with combinations of baseline FSH values and FSH levels over time. E2 concentrations less than 35 pg/ml were associated with lower BMD, but annual E2 measures and changes did not predict BMD loss. Testosterone, free androgen index, and dehydroepiandrosterone sulfate concentrations were not significantly associated with BMD loss. Spine and hip BMD losses during the menopause transition were most strongly related to the interaction between initial FSH levels and longitudinal FSH changes and not to E2 or androgen levels or changes.
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            Changes in bone resorption across the menopause transition: effects of reproductive hormones, body size, and ethnicity.

            Our objective was to characterize changes in bone resorption in relation to the final menstrual period (FMP), reproductive hormones, body mass index (BMI), and ethnicity.
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              Silicate modulates the cross-talk between osteoblasts (SaOS-2) and osteoclasts (RAW 264.7 cells): inhibition of osteoclast growth and differentiation.

              It has been shown that inorganic monomeric and polymeric silica/silicate, in the presence of the biomineralization cocktail, increases the expression of osteoprotegerin (OPG) in osteogenic SaOS-2 sarcoma cells in vitro. In contrast, silicate does not affect the steady-state gene expression level of the osteoclastogenic ligand receptor activator of NF-κB ligand (RANKL). In turn it can be expected that the concentration ratio of the mediators OPG/RANKL increases in the presence of silicate. In addition, silicate enhances the growth potential of SaOS-2 cells in vitro, while it causes no effect on RAW 264.7 cells within a concentration range of 10-100 µM. Applying a co-cultivation assay system, using SaOS-2 cells and RAW 264.7 cells, it is shown that in the presence of 10 µM silicate the number of RAW 264.7 cells in general, and the number of TRAP(+) RAW 264.7 cells in particular markedly decreases. The SaOS-2 cells retain their capacity of differential gene expression of OPG and RANKL in favor of OPG after exposure to silicate. It is concluded that after exposure of the cells to silicate a factor(s) is released from SaOS-2 cells that causes a significant inhibition of osteoclastogenesis of RAW 264.7 cells. It is assumed that it is an increased secretion of the cytokine OPG that is primarily involved in the reduction of the osteoclastogenesis of the RAW 264.7 cells. It is proposed that silicate might have the potential to stimulate osteogenesis in vivo and perhaps to ameliorate osteoporotic disorders. Copyright © 2012 Wiley Periodicals, Inc.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                4 August 2015
                2015
                : 10
                : 8
                : e0134986
                Affiliations
                [1 ]Department of Endocrinology, Affiliated Hospital of Weifang Medical University, Weifang, Shandong Province, China
                [2 ]Department of Endocrinology, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong Province, China
                [3 ]Shandong Clinical Medical Center of Endocrinology and Metabolism, Jinan, Shandong Province, China
                [4 ]Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, Shandong Province, China
                University of Pecs Medical School, HUNGARY
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: JX JJZ QBG. Performed the experiments: JW WWZ CXY XZ HQZ. Analyzed the data: JW WWZ CXY JX. Contributed reagents/materials/analysis tools: JW WWZ CXY. Wrote the paper: JW WWZ.

                Article
                PONE-D-15-14638
                10.1371/journal.pone.0134986
                4524683
                26241313
                4586256f-c159-4167-8932-31f2da855973
                Copyright @ 2015

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                History
                : 4 April 2015
                : 15 July 2015
                Page count
                Figures: 3, Tables: 4, Pages: 11
                Funding
                This work was supported by the National Natural Science Foundation (81370892, http://www.nsfc.gov.cn/), the Technology Development Plan Project of Shandong Province (2012GSF11823, http://www.sdstc.gov.cn/) and the Shandong Province Young and Middle-Aged Scientists Research Awards Fund (2007BS03004, http://www.sdstc.gov.cn/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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