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      The Antagonist of Retinoic Acid Receptor α, ER-50891 Antagonizes the Inhibitive Effect of All-Trans Retinoic Acid and Rescues Bone Morphogenetic Protein 2-Induced Osteoblastogenic Differentiation

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          Abstract

          Background

          Hypervitaminosis A, alcoholism or medical treatment for acute promyelocytic leukaemia may cause unphysiologically high accumulation of all-trans retinoic acid (ATRA), which could inhibit osteoblastogenesis, thereby triggering osteoporosis. We have shown that bone morphogenetic protein-2 (BMP-2) can only partially antagonize the inhibitive effects of ATRA. In this study, we hypothesized that antagonists of retinoic acid receptors (RARs) could further antagonize the inhibitive effect of ATRA and rescue BMP2-induced osteoblastogenesis.

          Materials and Methods

          We first screened the dose-dependent effects of the specific antagonists of RAR α, β and γ and transforming growth factor-beta receptor (ER-50891, LE-135, MM11253, and SB-43142, respectively) on ATRA-induced inhibition of the total cell metabolic activity and proliferation of preosteoblasts. We selected ER-50891 and tested its effects on osteoblastogenesis with the presence or absence of 1 μM ATRA and/or 200 ng/mL BMP-2. We measured the following parameters: Alkaline phosphatase activity (ALP), osteocalcin (OCN) expression and extracellular matrix mineralization as well as the level of phosphorylated Smad1/5.

          Results

          ER-50891 but not LE-135, MM11253, or SB-431542 significantly antagonized the inhibition of ATRA and enhanced the total cell metabolic activity and proliferation of preosteoblasts. Dose-dependent assays show ER-50891 could also rescue ATRA inhibited OCN expression and mineralization with or without the induction of BMP. ER-50891 also suppressed the ALP activity that was synergistically enhanced by BMP and ATRA. Neither ATRA, nor ER-50891 or their combination significantly affected the level of BMP-induced phosphorylated Smad1/5.

          Conclusion

          The antagonist of RARα, ER-50891 could significantly attenuate ATRA’s inhibitive effects on BMP 2-induced osteoblastogenesis.

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          Most cited references 56

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          Global statistics on alcohol, tobacco and illicit drug use: 2017 status report

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            Bone morphogenetic proteins in tissue engineering: the road from laboratory to clinic, part II (BMP delivery).

            Bone morphogenetic proteins (BMPs) are cytokines with a strong effect on bone and cartilage growth and with important roles during embryonic patterning and early skeletal formation. BMPs have promising potential for clinical bone and cartilage repair, working as powerful bone-inducing components in diverse tissue-engineering products. Synthetic polymers, natural origin polymers, inorganic materials and composites may be used as carriers for the delivery of BMPs. Carriers range from nanoparticles to complex three-dimensional (3D) scaffolds, membranes for tissue-guided regeneration, biomimetic surfaces and smart thermosensitive hydrogels. Current clinical uses include spinal fusion, healing of long bone defects and craniofacial and periodontal applications, amongst others. BMP-2 and BMP-7 have recently received approval by the US Food and Drug Administration (FDA) for specific clinical cases, delivered in absorbable collagen sponges. Considering the expanding number of publications in the field of BMPs, there are prospects of a brilliant future in the field of regenerative medicine of bone and cartilage with the use of BMPs.
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              Physiological insights into all-trans-retinoic acid biosynthesis.

               Joseph Napoli (2011)
              All-trans-retinoic acid (atRA) provides essential support to diverse biological systems and physiological processes. Epithelial differentiation and its relationship to cancer, and embryogenesis have typified intense areas of interest into atRA function. Recently, however, interest in atRA action in the nervous system, the immune system, energy balance and obesity has increased considerably, especially concerning postnatal function. atRA action depends on atRA biosynthesis: defects in retinoid-dependent processes increasingly relate to defects in atRA biogenesis. Considerable evidence indicates that physiological atRA biosynthesis occurs via a regulated process, consisting of a complex interaction of retinoid binding-proteins and retinoid recognizing enzymes. An accrual of biochemical, physiological and genetic data have identified specific functional outcomes for the retinol dehydrogenases, RDH1, RDH10, and DHRS9, as physiological catalysts of the first step in atRA biosynthesis, and for the retinal dehydrogenases RALDH1, RALDH2, and RALDH3, as catalysts of the second and irreversible step. Each of these enzymes associates with explicit biological processes mediated by atRA. Redundancy occurs, but seems limited. Cumulative data support a model of interactions among these enzymes with retinoid binding-proteins, with feedback regulation and/or control by atRA via modulating gene expression of multiple participants. The ratio apo-CRBP1/holo-CRBP1 participates by influencing retinol flux into and out of storage as retinyl esters, thereby modulating substrate to support atRA biosynthesis. atRA biosynthesis requires the presence of both an RDH and an RALDH: conversely, absence of one isozyme of either step does not indicate lack of atRA biosynthesis at the site. This article is part of a Special Issue entitled: Retinoid and Lipid Metabolism. © 2011 Elsevier B.V. All rights reserved.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                DDDT
                dddt
                Drug Design, Development and Therapy
                Dove
                1177-8881
                22 January 2020
                2020
                : 14
                : 297-308
                Affiliations
                [1 ]Department of Implantology, School and Hospital of Stomatology, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration , Jinan, Shandong Province, People’s Republic of China
                [2 ]College of Stomatology, North China University of Science and Technology , Tangshan, Hebei Province, People’s Republic of China
                [3 ]Key Laboratory of Oral Medicine, Guangzhou Institute of Oral Disease, Stomatology Hospital of Guangzhou Medical University, Guangzhou Medical University , Guangzhou, People’s Republic of China
                [4 ]Department of Oral Implantology and Prosthetic Dentistry, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam (UvA) and Vrije Universiteit Amsterdam (VU) , Amsterdam, The Netherlands
                [5 ]The Affiliated Stomatology Hospital, Zhejiang University School of Medicine , Hangzhou, Zhejiang Province, People’s Republic of China
                Author notes
                Correspondence: Gang Wu Department of Oral Implantology and Prosthetic Dentistry, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam (UvA) , Gustav Mahlerlaan 3004, Amsterdam1081LA, The NetherlandsTel +31 20 5980866Fax +31 20 5980333 Email g.wu@acta.nl
                Xin Xu Department of Implantology, School and Hospital of Stomatology, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration , No. 44-1, Wenhua Xi Road, Jinan, Shandong250012, People’s Republic of ChinaTel/Fax +86-531-88382923 Email xinxu@sdu.edu.cn
                [*]

                These authors contributed equally to this work

                Article
                215786
                10.2147/DDDT.S215786
                6985983
                32158187
                © 2020 Wang et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 6, References: 61, Pages: 12
                Categories
                Original Research

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