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      Oestrogen-deficiency induces bone loss by modulating CD14 + monocyte and CD4 + T cell DR3 expression and serum TL1A levels

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          Abstract

          Background

          Oestrogen-deficiency induced by menopause is associated with reduced bone density and primary osteoporosis, resulting in an increased risk of fracture. While the exact etiology of menopause-induced primary osteoporotic bone loss is not fully known, members of the tumour necrosis factor super family (TNFSF) are known to play a role. Recent studies have revealed that the TNFSF members death receptor 3 (DR3) and one of its ligands, TNF-like protein 1A (TL1A) have a key role in secondary osteoporosis; enhancing CD14 + peripheral blood mononuclear cell (PBMC) osteoclast formation and bone resorption. Whether DR3 and TL1A contribute towards bone loss in menopause-induced primary osteoporosis however, remains unknown.

          Methods

          To investigate this we performed flow cytometry analysis of DR3 expression on CD14 + PBMCs isolated from pre- and early post-menopausal females and late post-menopausal osteoporotic patients. Serum levels of TL1A, CCL3 and total MMP-9 were measured by ELISA. In vitro osteoclast differentiation assays were performed to determine CD14 + monocyte osteoclastogenic potential. In addition, splenic CD4 + T cell DR3 expression was investigated 1 week and 8 weeks post-surgery, using the murine ovariectomy model.

          Results

          In contrast to pre-menopausal females, CD14 + monocytes isolated from post-menopausal females were unable to induce DR3 expression. Serum TL1A levels were decreased approx. 2-fold in early post-menopausal females compared to pre-menopausal controls and post-menopausal osteoporotic females; no difference was observed between pre-menopausal and late post-menopausal osteoporotic females. Analysis of in vitro CD14 + monocyte osteoclastogenic potential revealed no significant difference between the post-menopausal and post-menopausal osteoporotic cohorts. Interestingly, in the murine ovariectomy model splenic CD4 + T cell DR3 expression was significantly increased at 1 week but not 8 weeks post-surgery when compared to the sham control.

          Conclusion

          Our results reveals for the first time that loss of oestrogen has a significant effect on DR3; decreasing expression on CD14 + monocytes and increasing expression on CD4 + T cells. These data suggest that while oestrogen-deficiency induced changes in DR3 expression do not affect late post-menopausal bone loss they could potentially have an indirect role in early menopausal bone loss through the modulation of T cell activity.

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          Most cited references26

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          Consensus development conference: diagnosis, prophylaxis, and treatment of osteoporosis.

          (1993)
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            From estrogen-centric to aging and oxidative stress: a revised perspective of the pathogenesis of osteoporosis.

            Estrogen deficiency has been considered the seminal mechanism of osteoporosis in both women and men, but epidemiological evidence in humans and recent mechanistic studies in rodents indicate that aging and the associated increase in reactive oxygen species (ROS) are the proximal culprits. ROS greatly influence the generation and survival of osteoclasts, osteoblasts, and osteocytes. Moreover, oxidative defense by the FoxO transcription factors is indispensable for skeletal homeostasis at any age. Loss of estrogens or androgens decreases defense against oxidative stress in bone, and this accounts for the increased bone resorption associated with the acute loss of these hormones. ROS-activated FoxOs in early mesenchymal progenitors also divert ss-catenin away from Wnt signaling, leading to decreased osteoblastogenesis. This latter mechanism may be implicated in the pathogenesis of type 1 and 2 diabetes and ROS-mediated adverse effects of diabetes on bone formation. Attenuation of Wnt signaling by the activation of peroxisome proliferator-activated receptor gamma by ligands generated from lipid oxidation also contributes to the age-dependent decrease in bone formation, suggesting a mechanistic explanation for the link between atherosclerosis and osteoporosis. Additionally, increased glucocorticoid production and sensitivity with advancing age decrease skeletal hydration and thereby increase skeletal fragility by attenuating the volume of the bone vasculature and interstitial fluid. This emerging evidence provides a paradigm shift from the "estrogen-centric" account of the pathogenesis of involutional osteoporosis to one in which age-related mechanisms intrinsic to bone and oxidative stress are protagonists and age-related changes in other organs and tissues, such as ovaries, accentuate them.
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              Estrogen deficiency induces bone loss by enhancing T-cell production of TNF-alpha.

              Estrogen deficiency induces bone loss by upregulating osteoclastogenesis by mechanisms not completely defined. We found that ovariectomy-enhanced T-cell production of TNF-alpha, which, acting through the TNF-alpha receptor p55, augments macrophage colony-stimulating factor-induced (M-CSF-induced) and RANKL-induced osteoclastogenesis. Ovariectomy failed to induce bone loss, stimulate bone resorption, or increase M-CSF- and RANKL-dependent osteoclastogenesis in T-cell deficient mice, establishing T cells as essential mediators of the bone-wasting effects of estrogen deficiency in vivo. These findings demonstrate that the ability of estrogen to target T cells, suppressing their production of TNF-alpha, is a key mechanism by which estrogen prevents osteoclastic bone resorption and bone loss.
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                Author and article information

                Contributors
                fras83@gmail.com
                StoneMD@cardiff.ac.uk
                TurtonJ@cardiff.ac.uk
                mccabel@msu.edu
                WangEC@cardiff.ac.uk
                williamsas@cardiff.ac.uk
                Journal
                BMC Musculoskelet Disord
                BMC Musculoskelet Disord
                BMC Musculoskeletal Disorders
                BioMed Central (London )
                1471-2474
                12 July 2019
                12 July 2019
                2019
                : 20
                : 326
                Affiliations
                [1 ]ISNI 0000 0001 0807 5670, GRID grid.5600.3, Division of Infection and Immunity, School of Medicine, , Cardiff University, ; Cardiff, UK
                [2 ]GRID grid.273109.e, University Hospital Llandough, Cardiff & Vale University Health Board, ; Cardiff, UK
                [3 ]ISNI 0000 0001 2150 1785, GRID grid.17088.36, Department of Physiology, , Michigan State University, ; East Lansing, MI USA
                Author information
                http://orcid.org/0000-0002-1156-6873
                Article
                2704
                10.1186/s12891-019-2704-z
                6626337
                31299941
                c4882b98-15fb-4dc3-a19e-11f05acd1f31
                © The Author(s). 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 31 August 2018
                : 3 July 2019
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100000341, Arthritis Research UK;
                Award ID: 18598
                Award ID: 18598
                Award ID: 18598
                Award Recipient :
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2019

                Orthopedics
                death receptor 3,dr3,tnf-like protein 1a,tl1a,menopause,oestrogen-deficiency,osteoporosis
                Orthopedics
                death receptor 3, dr3, tnf-like protein 1a, tl1a, menopause, oestrogen-deficiency, osteoporosis

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