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      Application of VEGFA and FGF-9 Enhances Angiogenesis, Osteogenesis and Bone Remodeling in Type 2 Diabetic Long Bone Regeneration

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          Abstract

          Although bone regeneration is typically a reliable process, type 2 diabetes is associated with impaired or delayed healing processes. In addition, angiogenesis, a crucial step in bone regeneration, is often altered in the diabetic state. In this study, different stages of bone regeneration were characterized in an unicortical bone defect model comparing transgenic type 2 diabetic ( db -/db - ) and wild type (WT) mice in vivo. We investigated angiogenesis, callus formation and bone remodeling at early, intermediate and late time points by means of histomorphometry as well as protein level analyses. In order to enhance bone regeneration, defects were locally treated with recombinant FGF-9 or VEGFA. Histomorphometry of aniline blue stained sections indicated that bone regeneration is significantly decreased in db -/db - as opposed to WT mice at intermediate (5 days post operation) and late stages (7 days post operation) of bone regeneration. Moreover, immunohistochemical analysis revealed significantly decreased levels of RUNX-2, PCNA, Osteocalcin and PECAM-1 in db -/db - defects. In addition, osteoclastogenesis is impaired in db -/db - indicating altered bone remodeling. These results indicate significant impairments in angiogenesis and osteogenesis in type 2 diabetic bones. Importantly, angiogenesis, osteogenesis and bone remodeling could be reconstituted by application of recombinant FGF-9 and, in part, by VEGFA application. In conclusion, our study demonstrates that type 2 diabetes affects angiogenesis, osteogenesis and subsequently bone remodeling, which in turn leads to decreased bone regeneration. These effects could be reversed by local application of FGF-9 and to a lesser degree VEGFA. These data could serve as a basis for future therapeutic applications aiming at improving bone regeneration in the type 2 diabetic patient population.

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          Most cited references57

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          VEGF couples hypertrophic cartilage remodeling, ossification and angiogenesis during endochondral bone formation.

          Hypertrophic chondrocytes in the epiphyseal growth plate express the angiogenic protein vascular endothelial growth factor (VEGF). To determine the role of VEGF in endochondral bone formation, we inactivated this factor through the systemic administration of a soluble receptor chimeric protein (Flt-(1-3)-IgG) to 24-day-old mice. Blood vessel invasion was almost completely suppressed, concomitant with impaired trabecular bone formation and expansion of hypertrophic chondrocyte zone. Recruitment and/or differentiation of chondroclasts, which express gelatinase B/matrix metalloproteinase-9, and resorption of terminal chondrocytes decreased. Although proliferation, differentiation and maturation of chondrocytes were apparently normal, resorption was inhibited. Cessation of the anti-VEGF treatment was followed by capillary invasion, restoration of bone growth, resorption of the hypertrophic cartilage and normalization of the growth plate architecture. These findings indicate that VEGF-mediated capillary invasion is an essential signal that regulates growth plate morphogenesis and triggers cartilage remodeling. Thus, VEGF is an essential coordinator of chondrocyte death, chondroclast function, extracellular matrix remodeling, angiogenesis and bone formation in the growth plate.
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            Vascular endothelial growth factor stimulates bone repair by promoting angiogenesis and bone turnover.

            Several growth factors are expressed in distinct temporal and spatial patterns during fracture repair. Of these, vascular endothelial growth factor, VEGF, is of particular interest because of its ability to induce neovascularization (angiogenesis). To determine whether VEGF is required for bone repair, we inhibited VEGF activity during secondary bone healing via a cartilage intermediate (endochondral ossification) and during direct bone repair (intramembranous ossification) in a novel mouse model. Treatment of mice with a soluble, neutralizing VEGF receptor decreased angiogenesis, bone formation, and callus mineralization in femoral fractures. Inhibition of VEGF also dramatically inhibited healing of a tibial cortical bone defect, consistent with our discovery of a direct autocrine role for VEGF in osteoblast differentiation. In separate experiments, exogenous VEGF enhanced blood vessel formation, ossification, and new bone (callus) maturation in mouse femur fractures, and promoted bony bridging of a rabbit radius segmental gap defect. Our results at specific time points during the course of healing underscore the role of VEGF in endochondral vs. intramembranous ossification, as well as skeletal development vs. bone repair. The responses to exogenous VEGF observed in two distinct model systems and species indicate that a slow-release formulation of VEGF, applied locally at the site of bone damage, may prove to be an effective therapy to promote human bone repair.
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              Type 1 diabetes

              Type 1 diabetes accounts for only about 5-10% of all cases of diabetes; however, its incidence continues to increase worldwide and it has serious short-term and long-term implications. The disorder has a strong genetic component, inherited mainly through the HLA complex, but the factors that trigger onset of clinical disease remain largely unknown. Management of type 1 diabetes is best undertaken in the context of a multidisciplinary health team and requires continuing attention to many aspects, including insulin administration, blood glucose monitoring, meal planning, and screening for comorbid conditions and diabetes-related complications. These complications consist of microvascular and macrovascular disease, which account for the major morbidity and mortality associated with type 1 diabetes. Newer treatment approaches have facilitated improved outcomes in terms of both glycaemic control and reduced risks for development of complications. Nonetheless, major challenges remain in the development of approaches to the prevention and management of type 1 diabetes and its complications.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                5 March 2015
                2015
                : 10
                : 3
                : e0118823
                Affiliations
                [1 ]Department of Plastic Surgery, BG University Hospital Bergmannsheil, Ruhr University Bochum, Bochum, Germany
                [2 ]Department of Plastic Surgery, BG Trauma Hospital Ludwigshafen, University of Heidelberg, Ludwigshafen, Germany
                [3 ]Research Centre for Experimental Orthopaedics, Heidelberg University Hospital, Heidelberg, Germany
                Université de Lyon—Université Jean Monnet, FRANCE
                Author notes

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

                Conceived and designed the experiments: CW JS MW MS SF TH BB. Performed the experiments: CW JS JMW SA. Analyzed the data: CW JS JMW MS SF TH WR SA UK ML BB. Contributed reagents/materials/analysis tools: WR UK ML BB. Wrote the paper: CW JS BB.

                ‡ These authors also contributed equally to this work.

                Article
                PONE-D-14-40454
                10.1371/journal.pone.0118823
                4350939
                25742620
                5356670d-e0c1-4f3f-8619-0047510015ce
                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
                : 10 September 2014
                : 9 January 2015
                Page count
                Figures: 7, Tables: 0, Pages: 19
                Funding
                Funding from the German Research Foundation (DFG) ( http://www.dfg.de/) # BE 4169/3-1. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Custom metadata
                All relevant data are within the paper and its Supporting Information files.

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