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      Magnesium and vitamin C supplementation attenuates steroid-associated osteonecrosis in a rat model

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          Abstract

          Magnesium (Mg)-based biometal attracts clinical applications due to its biodegradability and beneficial biological effects on tissue regeneration, especially in orthopaedics, yet the underlying anabolic mechanisms in relevant clinical disorders are lacking. The present study investigated the effect of magnesium (Mg) and vitamin C (VC) supplementation for preventing steroid-associated osteonecrosis (SAON) in a rat experimental model. In SAON rats, 50 mg/kg Mg, or 100 mg/kg VC, or combination, or water control was orally supplemented daily for 2 or 6 weeks respectively. Osteonecrosis was evaluated by histology. Serum Mg, VC, and bone turnover markers were measured. Microfil-perfused samples prepared for angiography and trabecular architecture were evaluated by micro-CT. Primary bone marrow cells were isolated from each group to evaluate their potentials in osteoblastogenesis and osteoclastogenesis. The mechanisms were tested in vitro. Histological evaluation showed SAON lesions in steroid treated groups. Mg and VC supplementation synergistically reduced the apoptosis of osteocytes and osteoclast number, and increased osteoblast surface. VC supplementation significantly increased the bone formation marker PINP, and the combination significantly decreased the bone resorption marker CTX. TNFα expression and oxidative injury were decreased in bone marrow in Mg/VC/combination group. Mg significantly increased the blood perfusion in proximal tibia and decreased the leakage particles in distal tibia 2 weeks after SAON induction. VC significantly elevated the osteoblast differentiation potential of marrow cells and improved the trabecular architecture. The combination supplementation significantly inhibited osteoclast differentiation potential of marrow cells. In vitro study showed promoting osteoblast differentiation effect of VC, and anti-inflammation and promoting angiogenesis effect of Mg with underlying mechanisms. Mg and VC supplementation could synergistically alleviate SAON in rats, indicating great translational potentials of metallic minerals for preventing SAON.

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          Implant-derived magnesium induces local neuronal production of CGRP to improve bone-fracture healing in rats.

          Yifeng Zhang, Jiankun Xu, Ye Ruan … (2016)
          Orthopedic implants containing biodegradable magnesium have been used for fracture repair with considerable efficacy; however, the underlying mechanisms by which these implants improve fracture healing remain elusive. Here we show the formation of abundant new bone at peripheral cortical sites after intramedullary implantation of a pin containing ultrapure magnesium into the intact distal femur in rats. This response was accompanied by substantial increases of neuronal calcitonin gene-related polypeptide-α (CGRP) in both the peripheral cortex of the femur and the ipsilateral dorsal root ganglia (DRG). Surgical removal of the periosteum, capsaicin denervation of sensory nerves or knockdown in vivo of the CGRP-receptor-encoding genes Calcrl or Ramp1 substantially reversed the magnesium-induced osteogenesis that we observed in this model. Overexpression of these genes, however, enhanced magnesium-induced osteogenesis. We further found that an elevation of extracellular magnesium induces magnesium transporter 1 (MAGT1)-dependent and transient receptor potential cation channel, subfamily M, member 7 (TRPM7)-dependent magnesium entry, as well as an increase in intracellular adenosine triphosphate (ATP) and the accumulation of terminal synaptic vesicles in isolated rat DRG neurons. In isolated rat periosteum-derived stem cells, CGRP induces CALCRL- and RAMP1-dependent activation of cAMP-responsive element binding protein 1 (CREB1) and SP7 (also known as osterix), and thus enhances osteogenic differentiation of these stem cells. Furthermore, we have developed an innovative, magnesium-containing intramedullary nail that facilitates femur fracture repair in rats with ovariectomy-induced osteoporosis. Taken together, these findings reveal a previously undefined role of magnesium in promoting CGRP-mediated osteogenic differentiation, which suggests the therapeutic potential of this ion in orthopedics.
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            Glucocorticoids act directly on osteoblasts and osteocytes to induce their apoptosis and reduce bone formation and strength.

            C. O’Brien, Dan Jia, Teresita Bellido … (2004)
            Whether the negative impact of excess glucocorticoids on the skeleton is due to direct effects on bone cells, indirect effects on extraskeletal tissues, or both is unknown. To determine the contribution of direct effects of glucocorticoids on osteoblastic/osteocytic cells in vivo, we blocked glucocorticoid action on these cells via transgenic expression of 11beta-hydroxysteroid dehydrogenase type 2, an enzyme that inactivates glucocorticoids. Osteoblast/osteocyte-specific expression was achieved by insertion of the 11beta-hydroxysteroid dehydrogenase type 2 cDNA downstream from the osteoblast-specific osteocalcin promoter. The transgene did not affect normal bone development or turnover as demonstrated by identical bone density, strength, and histomorphometry in adult transgenic and wild-type animals. Administration of excess glucocorticoids induced equivalent bone loss in wild-type and transgenic mice. As expected, cancellous osteoclasts were unaffected by the transgene. However, the increase in osteoblast apoptosis that occurred in wild-type mice was prevented in transgenic mice. Consistent with this, osteoblasts, osteoid area, and bone formation rate were significantly higher in glucocorticoid-treated transgenic mice compared with glucocorticoid-treated wild-type mice. Glucocorticoid-induced osteocyte apoptosis was also prevented in transgenic mice. Strikingly, the loss of vertebral compression strength observed in glucocorticoid-treated wild-type mice was prevented in the transgenic mice, despite equivalent bone loss. These results demonstrate for the first time that excess glucocorticoids directly affect bone forming cells in vivo. Furthermore, our results suggest that glucocorticoid-induced loss of bone strength results in part from increased death of osteocytes, independent of bone loss.
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              Linking oxidative stress to inflammation: Toll-like receptors.

              Roop Gill, Allan Tsung, Timothy Billiar (2010)
              Injury caused by oxidative stress occurs in many clinical scenarios involving ischemia and reperfusion such as organ transplantation, hemorrhagic shock (HS), myocardial infarction, and cerebral vascular accidents. Activation of the immune system as a result of disturbances in the redox state of cells seems to contribute to tissue and organ damage in these conditions. The link between oxidative stress and inflammatory pathways is poorly understood. Recently, Toll-like receptors (TLRs) have been shown to mediate the inflammatory response seen in experimental ischemia and reperfusion (I/R). The TLR family of receptors involved in alerting the innate immune system of danger seems to be activated by damage-associated molecular pattern molecules (DAMPs) that are released during conditions of oxidative stress. In this review, we examine the role of TLRs in various experimental models of oxidative stress such as HS and I/R. We also report on potential DAMPs that may interact with TLRs in mediating injury. Finally, potential mechanisms by which reactive oxygen species from NADPH oxidase can signal the commencement of inflammatory pathways through TLRs are explored. (c) 2009 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                De-Wei Zhao
                Ling Qin
                Journal
                Journal ID (nlm-ta): Biomaterials
                Journal ID (iso-abbrev): Biomaterials
                Title: Biomaterials
                Publisher: Elsevier Ltd.
                ISSN (Print): 0142-9612
                ISSN (Electronic): 1878-5905
                Publication date PMC-release: 31 January 2020
                Publication date (Print): April 2020
                Publication date (Electronic): 31 January 2020
                Volume: 238
                Page: 119828
                Affiliations
                [a ]Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong, Hong Kong, China
                [b ]Innovative Orthopaedic Biomaterial and Drug Translational Research Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong, China
                [c ]Translational Medicine R&D Center, Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
                [d ]Department of Biomedical Engineering, Faculty of Engineering, The Hong Kong Polytechnic University, Hong Kong, China
                [e ]Department of Orthopaedic Surgery, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning Province, China
                [f ]School of Biomedical Engineering, Sun Yat-sen University, Guangzhou, China
                Author notes
                [∗ ]Corresponding author. Rm74026, 5/F, Clinical Science Building, Prince of Wales Hospital, Shatin, Hong Kong Special Administrative Region. lingqin@ 123456cuhk.edu.hk
                [∗∗ ]Corresponding author (responsible for clinical data issues). Department of Orthopaedic Surgery, Affiliated Zhongshan Hospital of Dalian University, No. 6 Jiefang Street, Dalian, 116001, Liaoning, China. zhaodewei2000@ 123456163.com
                Article
                Publisher ID: S0142-9612(20)30074-0 Publisher ID: 119828
                DOI: 10.1016/j.biomaterials.2020.119828
                PMC ID: 7185815
                PubMed ID: 32045781
                SO-VID: d95085e1-f4ec-478c-8765-accd93618c26
                Copyright © © 2020 Elsevier Ltd. All rights reserved.
                License:

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

                History
                Date received : 4 October 2019
                Date revision received : 7 January 2020
                Date accepted : 25 January 2020
                Categories
                Subject: Article

                ScienceOpen disciplines: Biomaterials & Organic materials
                Keywords: corticosteroids,osteonecrosis,magnesium,vitamin c,preclinical studies
                Data availability:
                ScienceOpen disciplines: Biomaterials & Organic materials
                Keywords: corticosteroids, osteonecrosis, magnesium, vitamin c, preclinical studies

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