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      Dexamethasone Enhances Osteogenic Differentiation of Bone Marrow- and Muscle-Derived Stromal Cells and Augments Ectopic Bone Formation Induced by Bone Morphogenetic Protein-2

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          Abstract

          We evaluated whether dexamethasone augments the osteogenic capability of bone marrow-derived stromal cells (BMSCs) and muscle tissue-derived stromal cells (MuSCs), both of which are thought to contribute to ectopic bone formation induced by bone morphogenetic protein-2 (BMP-2), and determined the underlying mechanisms. Rat BMSCs and MuSCs were cultured in growth media with or without 10-7 M dexamethasone and then differentiated under osteogenic conditions with dexamethasone and BMP-2. The effects of dexamethasone on cell proliferation and osteogenic differentiation, and also on ectopic bone formation induced by BMP-2, were analyzed. Dexamethasone affected not only the proliferation rate but also the subpopulation composition of BMSCs and MuSCs, and subsequently augmented their osteogenic capacity during osteogenic differentiation. During osteogenic induction by BMP-2, dexamethasone also markedly affected cell proliferation in both BMSCs and MuSCs. In an in vivo ectopic bone formation model, bone formation in muscle-implanted scaffolds containing dexamethasone and BMP-2 was more than two fold higher than that in scaffolds containing BMP-2 alone. Our results suggest that dexamethasone potently enhances the osteogenic capability of BMP-2 and may thus decrease the quantity of BMP-2 required for clinical application, thereby reducing the complications caused by excessive doses of BMP-2.

          Highlights: 1. Dexamethasone induced selective proliferation of bone marrow- and muscle-derived cells with higher differentiation potential. 2. Dexamethasone enhanced the osteogenic capability of bone marrow- and muscle-derived cells by altering the subpopulation composition. 3. Dexamethasone augmented ectopic bone formation induced by bone morphogenetic protein-2.

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          Osteogenic differentiation of purified, culture-expanded human mesenchymal stem cells in vitro.

          Neelam Jaiswal, Stephen E. Haynesworth, Arnold I. Caplan … (1997)
          Human bone marrow contains a population of cells capable of differentiating along multiple mesenchymal cell lineages. Recently, techniques for the purification and culture-expansion of these human marrow-derived Mesenchymal Stem Cells (MSCs) have been developed. The goals of the current study were to establish a reproducible system for the in vitro osteogenic differentiation of human MSCs, and to characterize the effect of changes in the microenvironment upon the process. MSCs derived from 2nd or 3rd passage were cultured for 16 days in various base media containing 1 to 1000 nM dexamethasone (Dex), 0.01 to 4 mM L-ascorbic acid-2-phosphate (AsAP) or 0.25 mM ascorbic acid, and 1 to 10 mM beta-glycerophosphate (beta GP). Optimal osteogenic differentiation, as determined by osteoblastic morphology, expression of alkaline phosphatase (APase), reactivity with anti-osteogenic cell surface monoclonal antibodies, modulation of osteocalcin mRNA production, and the formation of a mineralized extracellular matrix containing hydroxyapatite was achieved with DMEM base medium plus 100 nM Dex, 0.05 mM AsAP, and 10 mM beta GP. The formation of a continuously interconnected network of APase-positive cells and mineralized matrix supports the characterization of this progenitor population as homogeneous. While higher initial seeding densities did not affect cell number of APase activity, significantly more mineral was deposited in these cultures, suggesting that events which occur early in the differentiation process are linked to end-stage phenotypic expression. Furthermore, cultures allowed to concentrate their soluble products in the media produced more mineralized matrix, thereby implying a role for autocrine or paracrine factors synthesized by human MSCs undergoing osteoblastic lineage progression. This culture system is responsive to subtle manipulations including the basal nutrient medium, dose of physiologic supplements, cell seeding density, and volume of tissue culture medium. Cultured human MSCs provide a useful model for evaluating the multiple factors responsible for the step-wise progression of cells from undifferentiated precursors to secretory osteoblasts, and eventually terminally differentiated osteocytes.
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            A critical review of recombinant human bone morphogenetic protein-2 trials in spinal surgery: emerging safety concerns and lessons learned.

            Eugene Carragee, Eric L Hurwitz, Bradley Weiner (2011)
            Increasingly, reports of frequent and occasionally catastrophic complications associated with use of recombinant human bone morphogenetic protein-2 (rhBMP-2) in spinal fusion surgeries are being published. In the original peer review, industry-sponsored publications describing the use of rhBMP-2 in spinal fusion, adverse events of these types and frequency were either not reported at all or not reported to be associated with rhBMP-2 use. Some authors and investigators have suggested that these discrepancies were related to inadequate peer review and editorial oversight. To compare the conclusions regarding the safety and related efficacy published in the original rhBMP-2 industry-sponsored trials with subsequently available Food and Drug Administration (FDA) data summaries, follow-up publications, and administrative and organizational databases. Systematic review. Results and conclusions from original industry-sponsored rhBMP-2 publications regarding safety and related efficacy were compared with available FDA data summaries, follow-up publications, and administrative and organizational database analyses. There were 13 original industry-sponsored rhBMP-2 publications regarding safety and efficacy, including reports and analyses of 780 patients receiving rhBMP-2 within prospective controlled study protocols. No rhBMP-2-associated adverse events (0%) were reported in any of these studies (99% confidence interval of adverse event rate <0.5%). The study designs of the industry-sponsored rhBMP-2 trials for use in posterolateral fusions and posterior lateral interbody fusion were found to have potential methodological bias against the control group. The reported morbidity of iliac crest donor site pain was also found to have serious potential design bias. Comparative review of FDA documents and subsequent publications revealed originally unpublished adverse events and internal inconsistencies. From this review, we suggest an estimate of adverse events associated with rhBMP-2 use in spine fusion ranging from 10% to 50% depending on approach. Anterior cervical fusion with rhBMP-2 has an estimated 40% greater risk of adverse events with rhBMP-2 in the early postoperative period, including life-threatening events. After anterior interbody lumbar fusion rates of implant displacement, subsidence, infection, urogenital events, and retrograde ejaculation were higher after using rhBMP-2 than controls. Posterior lumbar interbody fusion use was associated with radiculitis, ectopic bone formation, osteolysis, and poorer global outcomes. In posterolateral fusions, the risk of adverse effects associated with rhBMP-2 use was equivalent to or greater than that of iliac crest bone graft harvesting, and 15% to 20% of subjects reported early back pain and leg pain adverse events; higher doses of rhBMP-2 were also associated with a greater apparent risk of new malignancy. Level I and Level II evidence from original FDA summaries, original published data, and subsequent studies suggest possible study design bias in the original trials, as well as a clear increased risk of complications and adverse events to patients receiving rhBMP-2 in spinal fusion. This risk of adverse events associated with rhBMP-2 is 10 to 50 times the original estimates reported in the industry-sponsored peer-reviewed publications. Copyright © 2011 Elsevier Inc. All rights reserved.
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              Use of a new adhesive film for the preparation of multi-purpose fresh-frozen sections from hard tissues, whole-animals, insects and plants.

              Tadafumi Kawamoto (2003)
              A method for preparing thin fresh-frozen sections from large samples and hard tissues is described and the applications are shown. A new adhesive film is introduced to produce the frozen sections. The sample is frozen in a cooled hexane or liquid nitrogen, and then freeze-embedded with 4-5% carboxymethyl cellulose (CMC) in the coolant. A specially prepared adhesive film is fastened to the cut surface of the sample in order to support the section and cut slowly with a disposable tungsten carbide blade. The adhesive film is made of a thin plastic film and an adhesive before use. This method produces 2-microm thick fresh-frozen sections from a large sample, bone or tooth. The "film-section" i.e. the section attached to the adhesive film, can be used for many types of studies such as histology, general histochemistry, enzyme histochemistry, immunohistochemistry, in situ hybridization, elemental analysis, and autoradiography for water-soluble materials. Immunohistochemistry and in situ hybridization can be carried out with nonfixed and undecalcified sections. The section on the adhesive film can be transferred to a glass slide and mounted under a cover slip, and stained sections can be examined with an optical microscope at high magnification. This method is also useful for preparing frozen sections from samples of fish, insects, and plants. Furthermore, samples of particular areas can be collected from the film-section by means of a laser microdissection technique. The multiple possible applications of the adhesive film render it highly useful for studies in biological and medico-dental fields.
              Article 0 comments Cited 192 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Xing-Ming Shi: Role: Academic Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2015
                Publication date (Electronic): 6 February 2015
                Volume: 10
                Issue: 2
                Electronic Location Identifier: e0116462
                Affiliations
                [1 ]Department of Orthopaedic and Spinal Surgery, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
                [2 ]Global Center of Excellence (GCOE) Program, International Research Center for Molecular Science in Tooth and Bone Diseases, Tokyo Medical and Dental University, Tokyo, Japan
                [3 ]Hyperbaric Medical Center, University Hospital of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
                [4 ]National Institute of Advanced Industrial Science and Technology, Ibaraki, Japan
                [5 ]Department of Orthopaedic Research and Development, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
                Georgia Regents University, UNITED STATES
                Author notes

                Competing Interests: The authors have read the journal’s policy and the authors of this manuscript have the following competing interests: this study was partially supported by grants from the Olympus Corporation. This does not alter the authors’ adherence to PLOS ONE policies on sharing data and materials.

                Conceived and designed the experiments: MY T. Yoshii AO SS. Performed the experiments: MY T. Yamada TT TM WX MH HY SS. Analyzed the data: MY T. Yamada TT TM MH HY SS. Contributed reagents/materials/analysis tools: TU SS. Wrote the paper: MY SS.

                Article
                Publisher ID: PONE-D-14-22754
                DOI: 10.1371/journal.pone.0116462
                PMC ID: 4319911
                PubMed ID: 25659106
                SO-VID: 6c37db22-5365-4e10-b31d-0e1f2b66f0b2
                Copyright statement: Copyright @ 2015
                License:

                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
                Date received : 23 May 2014
                Date accepted : 10 December 2014
                Page count
                Figures: 6, Tables: 1, Pages: 23
                Funding
                This study was partially supported by grants from the Japanese Ministry of Health, Labor and Welfare and by Olympus Corporation. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
                Categories
                Subject: Research Article
                Custom metadata
                Data Availability All relevant data are within the paper.

                ScienceOpen disciplines: Uncategorized
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                ScienceOpen disciplines: Uncategorized

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