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      Preservation of alveolar ridge after tooth extraction with hypoxia-inducible factor-1α protein in a dog model

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          Abstract

          Hypoxia-inducible factor (HIF)-1α protein, which is upregulated by hypoxia, serves an important role in angiogenesis during osteogenesis. The aim of the present study was to investigate the effect of HIF-1α on alveolar ridge preservation in a dog tooth extraction model. Six beagle dogs were used in the present study. The second and fourth premolar teeth of the lower jaws on both sides were extracted. Two unilateral extraction sockets were randomly selected and filled with Bio-Oss and Bio-Oss + HIF-1α. The contralateral sockets remained unfilled and served as the negative control. Micro-computed tomography examination and histological staining were performed to examine the difference of new bone formation among the three groups. Western blotting and reverse transcription-quantitative polymerase chain reaction analysis were used to detect the expression levels of osteogenesis- and angiogenesis-associated genes in the bone tissues of the three groups. Twelve weeks post-surgery, trabecular bone formation in the Bio-Oss + HIF-1α group was significantly increased compared with the other groups. The expression levels of osteogenesis-associated genes (runt-related transcription factor 2, osteoblast-specific transcription factor osterix and osteocalcin) and angiogenesis-associated genes (HIF-1α and vascular endothelial growth factor) were all significantly increased in the Bio-Oss + HIF-1α group compared with the other two groups (P<0.05). The present results indicated that Bio-Oss with HIF-1α can promote osteogenesis and angiogenesis in vivo and may be used as an effective treatment for the preservation of the alveolar ridge.

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          Most cited references30

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          Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1.

          Hypoxia-inducible factor 1 (HIF-1) activates erythropoietin gene transcription in Hep3B cells subjected to hypoxia. HIF-1 activity is also induced by hypoxia in non-erythropoietin-producing cells, suggesting a more general regulatory role. We now report that RNAs encoding the glycolytic enzymes aldolase A (ALDA), phosphoglycerate kinase 1 (PGK1), and pyruvate kinase M were induced by exposure of Hep3B or HeLa cells to inducers of HIF-1 (1% O2, cobalt chloride, or desferrioxamine), whereas cycloheximide blocked induction of glycolytic RNAs and HIF-1 activity. Oligonucleotides from the ALDA, PGK1, enolase 1, lactate dehydrogenase A, and phosphofructokinase L (PFKL) genes, containing sequences similar to the HIF-1 binding site in the erythropoietin enhancer, specifically bound HIF-1 present in crude nuclear extracts or affinity-purified preparations. Sequences from the ALDA, PFKL, and PGK1 genes containing HIF-1 binding sites mediated hypoxia-inducible transcription in transient expression assays. These results support the role of HIF-1 as a mediator of adaptive responses to hypoxia that underlie cellular and systemic oxygen homeostasis.
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            The hypoxia-inducible factor alpha pathway couples angiogenesis to osteogenesis during skeletal development.

            Skeletal development and turnover occur in close spatial and temporal association with angiogenesis. Osteoblasts are ideally situated in bone to sense oxygen tension and respond to hypoxia by activating the hypoxia-inducible factor alpha (HIF alpha) pathway. Here we provide evidence that HIF alpha promotes angiogenesis and osteogenesis by elevating VEGF levels in osteoblasts. Mice overexpressing HIF alpha in osteoblasts through selective deletion of the von Hippel-Lindau gene (Vhl) expressed high levels of Vegf and developed extremely dense, heavily vascularized long bones. By contrast, mice lacking Hif1a in osteoblasts had the reverse skeletal phenotype of that of the Vhl mutants: long bones were significantly thinner and less vascularized than those of controls. Loss of Vhl in osteoblasts increased endothelial sprouting from the embryonic metatarsals in vitro but had little effect on osteoblast function in the absence of blood vessels. Mice lacking both Vhl and Hif1a had a bone phenotype intermediate between those of the single mutants, suggesting overlapping functions of HIFs in bone. These studies suggest that activation of the HIF alpha pathway in developing bone increases bone modeling events through cell-nonautonomous mechanisms to coordinate the timing, direction, and degree of new blood vessel formation in bone.
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              The roles of vascular endothelial growth factor in bone repair and regeneration.

              Vascular endothelial growth factor-A (VEGF) is one of the most important growth factors for regulation of vascular development and angiogenesis. Since bone is a highly vascularized organ and angiogenesis plays an important role in osteogenesis, VEGF also influences skeletal development and postnatal bone repair. Compromised bone repair and regeneration in many patients can be attributed to impaired blood supply; thus, modulation of VEGF levels in bones represents a potential strategy for treating compromised bone repair and improving bone regeneration. This review (i) summarizes the roles of VEGF at different stages of bone repair, including the phases of inflammation, endochondral ossification, intramembranous ossification during callus formation and bone remodeling; (ii) discusses different mechanisms underlying the effects of VEGF on osteoblast function, including paracrine, autocrine and intracrine signaling during bone repair; (iii) summarizes the role of VEGF in the bone regenerative procedure, distraction osteogenesis; and (iv) reviews evidence for the effects of VEGF in the context of repair and regeneration techniques involving the use of scaffolds, skeletal stem cells and growth factors.
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                Author and article information

                Journal
                Exp Ther Med
                Exp Ther Med
                ETM
                Experimental and Therapeutic Medicine
                D.A. Spandidos
                1792-0981
                1792-1015
                April 2019
                22 February 2019
                22 February 2019
                : 17
                : 4
                : 2913-2920
                Affiliations
                [1 ]Department of Stomatology, Shanghai East Hospital Affiliated with Tongji University, Shanghai 200120, P.R. China
                [2 ]Department of Orthodontics, Shanghai Stomatological Hospital, Fudan University, Shanghai 200031, P.R. China
                [3 ]Oral Biomedical Engineering Laboratory, Shanghai Stomatological Hospital, Fudan University, Shanghai 200031, P.R. China
                [4 ]Department of Oral Surgery, Shanghai Stomatological Hospital, Fudan University, Shanghai 200031, P.R. China
                Author notes
                Correspondence to: Dr Yuan Luo, Department of Oral Surgery, Shanghai Stomatological Hospital, Fudan University, 1258 Middle Fuxing Road, Shanghai 200031, P.R. China, E-mail: yuanluo@ 123456126.com
                Dr Yuehua Liu, Department of Orthodontics, Shanghai Stomatological Hospital, Fudan University, 1258 Middle Fuxing Road, Shanghai 200031, P.R. China, E-mail: liuyuehua@ 123456fudan.edu.cn
                Article
                ETM-0-0-7301
                10.3892/etm.2019.7301
                6434234
                eb838a22-386f-47ee-afe7-c604aa7855f5
                Copyright: © Tan et al.

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

                History
                : 04 April 2018
                : 26 October 2018
                Categories
                Articles

                Medicine
                alveolar ridge preservation,hypoxia-inducible factor-1α protein,osteogenesis,angiogenesis

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