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      Myeloid HIF1α Is Involved in the Extent of Orthodontically Induced Tooth Movement

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          Abstract

          During orthodontic tooth movement, transcription factor hypoxia-inducible factor 1α (HIF1α) is stabilised in the periodontal ligament. While HIF1α in periodontal ligament fibroblasts can be stabilised by mechanical compression, in macrophages pressure application alone is not sufficient to stabilise HIF1α. The present study was conducted to investigate the role of myeloid HIF1α during orthodontic tooth movement. Orthodontic tooth movement was performed in wildtype and Hif1α Δmyel mice lacking HIF1α expression in myeloid cells. Subsequently, µCT images were obtained to determine periodontal bone loss, extent of orthodontic tooth movement and bone density. RNA was isolated from the periodontal ligament of the control side and the orthodontically treated side, and the expression of genes involved in bone remodelling was investigated. The extent of tooth movement was increased in Hif1α Δmyel mice. This may be due to the lower bone density of the Hif1α Δmyel mice. Deletion of myeloid Hif1α was associated with increased expression of Ctsk and Acp5, while both Rankl and its decoy receptor Opg were increased. HIF1α from myeloid cells thus appears to play a regulatory role in orthodontic tooth movement.

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          HIF-1α pathway: role, regulation and intervention for cancer therapy

          Hypoxia-inducible factor-1 (HIF-1) has been recognized as an important cancer drug target. Many recent studies have provided convincing evidences of strong correlation between elevated levels of HIF-1 and tumor metastasis, angiogenesis, poor patient prognosis as well as tumor resistance therapy. It was found that hypoxia (low O2 levels) is a common character in many types of solid tumors. As an adaptive response to hypoxic stress, hypoxic tumor cells activate several survival pathways to carry out their essential biological processes in different ways compared with normal cells. Recent advances in cancer biology at the cellular and molecular levels highlighted the HIF-1α pathway as a crucial survival pathway for which novel strategies of cancer therapy could be developed. However, targeting the HIF-1α pathway has been a challenging but promising progresses have been made in the past twenty years. This review summarizes the role and regulation of the HIF-1α in cancer, and recent therapeutic approaches targeting this important pathway.
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            Functions of RANKL/RANK/OPG in bone modeling and remodeling.

            The discovery of the RANKL/RANK/OPG system in the mid 1990s for the regulation of bone resorption has led to major advances in our understanding of how bone modeling and remodeling are regulated. It had been known for many years before this discovery that osteoblastic stromal cells regulated osteoclast formation, but it had not been anticipated that they would do this through expression of members of the TNF superfamily: receptor activator of NF-kappaB ligand (RANKL) and osteoprotegerin (OPG), or that these cytokines and signaling through receptor activator of NF-kappaB (RANK) would have extensive functions beyond regulation of bone remodeling. RANKL/RANK signaling regulates osteoclast formation, activation and survival in normal bone modeling and remodeling and in a variety of pathologic conditions characterized by increased bone turnover. OPG protects bone from excessive resorption by binding to RANKL and preventing it from binding to RANK. Thus, the relative concentration of RANKL and OPG in bone is a major determinant of bone mass and strength. Here, we review our current understanding of the role of the RANKL/RANK/OPG system in bone modeling and remodeling.
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              HIF-1alpha is essential for myeloid cell-mediated inflammation.

              Granulocytes and monocytes/macrophages of the myeloid lineage are the chief cellular agents of innate immunity. Here, we have examined the inflammatory response in mice with conditional knockouts of the hypoxia responsive transcription factor HIF-1alpha, its negative regulator VHL, and a known downstream target, VEGF. We find that activation of HIF-1alpha is essential for myeloid cell infiltration and activation in vivo through a mechanism independent of VEGF. Loss of VHL leads to a large increase in acute inflammatory responses. Our results show that HIF-1alpha is essential for the regulation of glycolytic capacity in myeloid cells: when HIF-1alpha is absent, the cellular ATP pool is drastically reduced. The metabolic defect results in profound impairment of myeloid cell aggregation, motility, invasiveness, and bacterial killing. This role for HIF-1alpha demonstrates its direct regulation of survival and function in the inflammatory microenvironment.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Biomedicines
                Biomedicines
                biomedicines
                Biomedicines
                MDPI
                2227-9059
                08 July 2021
                July 2021
                : 9
                : 7
                : 796
                Affiliations
                [1 ]Department of Orthodontics, University Medical Centre of Regensburg, D-93053 Regensburg, Germany; nadine.strassmair@ 123456stud.uni-regensburg.de (N.S.); eva.paddenberg@ 123456ukr.de (E.P.); peter.proff@ 123456ukr.de (P.P.); agnes.schroeder@ 123456ukr.de (A.S.)
                [2 ]Department of Operative Dentistry and Periodontology, University Medical Centre of Regensburg, D-93053 Regensburg, Germany; fabian.cieplik@ 123456ukr.de
                [3 ]Institute of Microbiology and Hygiene, University Medical Centre of Regensburg, D-93053 Regensburg, Germany; jonathan.jantsch@ 123456ukr.de
                Author notes
                [* ]Correspondence: christian.kirschneck@ 123456ukr.de ; Tel.: +49-941-944-6093
                Author information
                https://orcid.org/0000-0001-9473-8724
                https://orcid.org/0000-0002-1750-7380
                https://orcid.org/0000-0001-6010-9831
                Article
                biomedicines-09-00796
                10.3390/biomedicines9070796
                8301336
                34356859
                16b44adb-180c-4a04-a8cf-d8be6aaafccd
                © 2021 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( https://creativecommons.org/licenses/by/4.0/).

                History
                : 08 June 2021
                : 07 July 2021
                Categories
                Article

                orthodontic tooth movement,hif1α,macrophage,µct
                orthodontic tooth movement, hif1α, macrophage, µct

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