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      Dose-Dependent Effect of Estrogen Suppresses the Osteo-Adipogenic Transdifferentiation of Osteoblasts via Canonical Wnt Signaling Pathway

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          Abstract

          Fat infiltration within marrow cavity is one of multitudinous features of estrogen deficiency, which leads to a decline in bone formation functionality. The origin of this fat is unclear, but one possibility is that it is derived from osteoblasts, which transdifferentiate into adipocytes that produce bone marrow fat. We examined the dose-dependent effect of 17β-estradiol on the ability of MC3T3-E1 cells and murine bone marrow-derived mesenchymal stem cell (BMMSC)-derived osteoblasts to undergo osteo-adipogenic transdifferentiation. We found that 17β-estradiol significantly increased alkaline phosphatase activity (P<0.05); calcium deposition; and Alp, Col1a1, Runx2, and Ocn expression levels dose-dependently. By contrast, 17β-estradiol significantly decreased the number and size of lipid droplets, and Fabp4 and PPARγ expression levels during osteo-adipogenic transdifferentiation (P<0.05). Moreover, the expression levels of brown adipocyte markers ( Myf5, Elovl3, and Cidea) and undifferentiated adipocyte markers ( Dlk1, Gata2, and Wnt10b) were also affected by 17β-estradiol during osteo-adipogenic transdifferentiation. Western blotting and immunostaining further showed that canonical Wnt signaling can be activated by estrogen to exert its inhibitory effect of osteo-adipogenesis. This is the first study to demonstrate the dose-dependent effect of 17β-estradiol on the osteo-adipogenic transdifferentiation of MC3T3-E1 cells and BMMSCs likely via canonical Wnt signaling. In summary, our results indicate that osteo-adipogenic transdifferentiation modulated by canonical Wnt signaling pathway in bone metabolism may be a new explanation for the gradually increased bone marrow fat in estrogen-inefficient condition.

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          LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development.

          In humans, low peak bone mass is a significant risk factor for osteoporosis. We report that LRP5, encoding the low-density lipoprotein receptor-related protein 5, affects bone mass accrual during growth. Mutations in LRP5 cause the autosomal recessive disorder osteoporosis-pseudoglioma syndrome (OPPG). We find that OPPG carriers have reduced bone mass when compared to age- and gender-matched controls. We demonstrate LRP5 expression by osteoblasts in situ and show that LRP5 can transduce Wnt signaling in vitro via the canonical pathway. We further show that a mutant-secreted form of LRP5 can reduce bone thickness in mouse calvarial explant cultures. These data indicate that Wnt-mediated signaling via LRP5 affects bone accrual during growth and is important for the establishment of peak bone mass.
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            Regulation of bone mass by Wnt signaling.

            Wnt proteins are a family of secreted proteins that regulate many aspects of cell growth, differentiation, function, and death. Considerable progress has been made in our understanding of the molecular links between Wnt signaling and bone development and remodeling since initial reports that mutations in the Wnt coreceptor low-density lipoprotein receptor-related protein 5 (LRP5) are causally linked to alterations in human bone mass. Of the pathways activated by Wnts, it is signaling through the canonical (i.e., Wnt/beta-catenin) pathway that increases bone mass through a number of mechanisms including renewal of stem cells, stimulation of preosteoblast replication, induction of osteoblastogenesis, and inhibition of osteoblast and osteocyte apoptosis. This pathway is an enticing target for developing drugs to battle skeletal diseases as Wnt/beta-catenin signaling is composed of a series of molecular interactions that offer potential places for pharmacological intervention. In considering opportunities for anabolic drug discovery in this area, one must consider multiple factors, including (a) the roles of Wnt signaling for development, remodeling, and pathology of bone; (b) how pharmacological interventions that target this pathway may specifically treat osteoporosis and other aspects of skeletal health; and (c) whether the targets within this pathway are amenable to drug intervention. In this Review we discuss the current understanding of this pathway in terms of bone biology and assess whether targeting this pathway might yield novel therapeutics to treat typical bone disorders.
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              Adipocyte tissue volume in bone marrow is increased with aging and in patients with osteoporosis.

              Aging of the human skeleton is characterized by decreased bone formation and bone mass and these changes are more pronounced in patients with osteoporosis. As osteoblasts and adipocytes share a common precursor cell in the bone marrow, we hypothesized that decreased bone formation observed during aging and in patients with osteoporosis is the result of enhanced adipognesis versus osteoblastogenesis from precursor cells in the bone marrow. Thus, we examined iliac crest bone biopsies obtained from 53 healthy normal individuals (age 30-100) and 26 patients with osteoporosis (age 52-92). Adipose tissue volume fraction (AV), hematopoietic tissue volume fraction (HV) and trabecular bone volume fraction (BV) were quantitated as a percentage of total tissue volume fraction (TV) (calculated as BV + AV + HV) using the point-counting method. We found an age-related increase in AV/TV (r = 0.53, P < 0.001, n = 53) and an age-related decline in BV/TV (r = -0.46, P < 0.001, n = 53) as well as in the HV/TV (r -0.318, P < 0.05, n = 53). There was an age-related inverse correlation between BV/TV and AV/TV (r = -0.58, P < 0.001). No significant correlation between the AV/TV and the body mass index (r = 0.06, n.s., n = 52) was detectable. Compared with age-matched controls, patients with osteoporosis exhibited an increased AV/TV (P < 0.05) and decreased BV/TV (P < 0.05) but no statistically significant difference in HV/TV. Our data support the hypothesis that with aging and in osteoporosis an enhanced adipogenesis is observed in the bone marrow and that these changes are inversely correlated to decreased trabecular bone volume. The cellular and molecular mechanisms mediating these changes remain to be determined.
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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, USA )
                1932-6203
                2014
                11 June 2014
                : 9
                : 6
                : e99137
                Affiliations
                [1 ]Institute of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, People’s Republic of China
                [2 ]Department of Orthopaedics, First Affiliated Hospital, Chengdu Medical College, Chengdu, People’s Republic of China
                The University of Hong Kong, Hong Kong
                Author notes

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

                Conceived and designed the experiments: BG LY ZJL. Performed the experiments: BG QH YSL BYW HYZ ZS. Analyzed the data: YSG XJL YHH JS. Contributed reagents/materials/analysis tools: JF JL LW. Wrote the paper: BG QH.

                Article
                PONE-D-14-09497
                10.1371/journal.pone.0099137
                4053448
                24918446
                8c8540ef-e807-4f1e-942b-540fdc988f5a
                Copyright @ 2014

                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
                : 11 March 2014
                : 11 May 2014
                Page count
                Pages: 11
                Funding
                This work was supported by the Ministry of Science and Technology of China (2011CB964703), the National High Technology Research and Development Program 863 (2012AA020502), and the China Postdoctoral Science Foundation (2012T50856), and the Program for Changjiang Scholars and Innovative Research Team in University (No. IRT1053). No benefits in any form have been or will be received from a commercial party directly or indirectly by the authors of this manuscript. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Biochemistry
                Metabolism
                Cell Biology
                Cellular Types
                Animal Cells
                Bone Marrow Cells
                Bone Marrow Stem Cells

                Uncategorized
                Uncategorized

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