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

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

  • Nat Med. 2016 Oct;22(10):1160-1169. doi: 10.1038/nm.4162.
Yifeng Zhang 1,  Jiankun Xu 1,  Ye Chun Ruan 2,  Mei Kuen Yu 2,  Micheal O'Laughlin 1,  Helen Wise 3,  Di Chen 4,  Li Tian 1,  Dufang Shi 1,  Jiali Wang 1,  Sihui Chen 1,  Jian Q Feng 5,  Dick Ho Kiu Chow 1,  Xinhui Xie 1,  Lizhen Zheng 1,  Le Huang 1,  Shuo Huang 1,  Kwoksui Leung 1,  Na Lu 6,  Lan Zhao 4,  Huafang Li 1,  Dewei Zhao 7,  Xia Guo 8,  Kaiming Chan 1,  Frank Witte 9 10,  Hsiao Chang Chan 2,  Yufeng Zheng 11,  Ling Qin 1 12
Affiliations

Affiliations

  • 1 Musculoskeletal Research Laboratory, Department of Orthopedics &Traumatology, The Chinese University of Hong Kong, Hong Kong, PR China.
  • 2 Epithelial Cell Biology Research Centre, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, PR China.
  • 3 School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, PR China.
  • 4 Department of Biochemistry, Rush University, Chicago, USA.
  • 5 Department of Biomedical Sciences, Baylor College of Dentistry, Texas A&M Health Science Center, Dallas, Texas, USA.
  • 6 Division of Life Science, The Hong Kong University of Science and Technology, Kowloon, Hong Kong, PR China.
  • 7 Department of Orthopedics, Dalian University Zhongshan Hospital, Dalian, PR China.
  • 8 Department of Rehabilitation Sciences, The Hong Kong Polytechnic University, Hong Kong, PR China.
  • 9 Julius Wolff Institute and Center for Musculoskeletal Surgery, Charité-Universitätsmedizin Berlin, Berlin, Germany.
  • 10 Berlin-Brandenburg Center for Regenerative Therapies, Charité-Universitätsmedizin Berlin, Berlin, Germany.
  • 11 Department of Materials Science and Engineering, College of Engineering, Peking University, Beijing, PR China.
  • 12 Translational Medicine Research &Development Center, Institute of Biomedical and Health Engineering, Shenzhen Institute of Advanced Technology, Shenzhen, PR China.
PMID: 27571347 DOI: 10.1038/nm.4162
Abstract

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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