title: Implant-derived magnesium induces local neuronal production of CGRP to improve bone-fracture healing in rats.
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.
authors: Musculoskeletal Research Laboratory, Department of Orthopedics &Traumatology, The Chinese University of Hong Kong, Hong Kong, PR China.
authors: Yifeng
authors: Y
authors: Zhang
authors: Musculoskeletal Research Laboratory, Department of Orthopedics &Traumatology, The Chinese University of Hong Kong, Hong Kong, PR China.
authors: Jiankun
authors: J
authors: Xu
authors: Epithelial Cell Biology Research Centre, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, PR China.
authors: Ye Chun
authors: YC
authors: Ruan
authors: Epithelial Cell Biology Research Centre, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, PR China.
authors: Mei Kuen
authors: MK
authors: Yu
authors: Musculoskeletal Research Laboratory, Department of Orthopedics &Traumatology, The Chinese University of Hong Kong, Hong Kong, PR China.
authors: Micheal
authors: M
authors: O'Laughlin
authors: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, PR China.
authors: Helen
authors: H
authors: Wise
authors: Department of Biochemistry, Rush University, Chicago, USA.
authors: Di
authors: D
authors: Chen
authors: Musculoskeletal Research Laboratory, Department of Orthopedics &Traumatology, The Chinese University of Hong Kong, Hong Kong, PR China.
authors: Li
authors: L
authors: Tian
authors: Musculoskeletal Research Laboratory, Department of Orthopedics &Traumatology, The Chinese University of Hong Kong, Hong Kong, PR China.
authors: Dufang
authors: D
authors: Shi
authors: Musculoskeletal Research Laboratory, Department of Orthopedics &Traumatology, The Chinese University of Hong Kong, Hong Kong, PR China.
authors: Jiali
authors: J
authors: Wang
authors: Musculoskeletal Research Laboratory, Department of Orthopedics &Traumatology, The Chinese University of Hong Kong, Hong Kong, PR China.
authors: Sihui
authors: S
authors: Chen
authors: Department of Biomedical Sciences, Baylor College of Dentistry, Texas A&M Health Science Center, Dallas, Texas, USA.
authors: Jian Q
authors: JQ
authors: Feng
authors: Musculoskeletal Research Laboratory, Department of Orthopedics &Traumatology, The Chinese University of Hong Kong, Hong Kong, PR China.
authors: Dick Ho Kiu
authors: 0000-0002-2836-3255
authors: DH
authors: Chow
authors: Musculoskeletal Research Laboratory, Department of Orthopedics &Traumatology, The Chinese University of Hong Kong, Hong Kong, PR China.
authors: Xinhui
authors: X
authors: Xie
authors: Musculoskeletal Research Laboratory, Department of Orthopedics &Traumatology, The Chinese University of Hong Kong, Hong Kong, PR China.
authors: Lizhen
authors: L
authors: Zheng
authors: Musculoskeletal Research Laboratory, Department of Orthopedics &Traumatology, The Chinese University of Hong Kong, Hong Kong, PR China.
authors: Le
authors: L
authors: Huang
authors: Musculoskeletal Research Laboratory, Department of Orthopedics &Traumatology, The Chinese University of Hong Kong, Hong Kong, PR China.
authors: Shuo
authors: S
authors: Huang
authors: Musculoskeletal Research Laboratory, Department of Orthopedics &Traumatology, The Chinese University of Hong Kong, Hong Kong, PR China.
authors: Kwoksui
authors: K
authors: Leung
authors: Division of Life Science, The Hong Kong University of Science and Technology, Kowloon, Hong Kong, PR China.
authors: Na
authors: N
authors: Lu
authors: Department of Biochemistry, Rush University, Chicago, USA.
authors: Lan
authors: L
authors: Zhao
authors: Musculoskeletal Research Laboratory, Department of Orthopedics &Traumatology, The Chinese University of Hong Kong, Hong Kong, PR China.
authors: Huafang
authors: H
authors: Li
authors: Department of Orthopedics, Dalian University Zhongshan Hospital, Dalian, PR China.
authors: Dewei
authors: D
authors: Zhao
authors: Department of Rehabilitation Sciences, The Hong Kong Polytechnic University, Hong Kong, PR China.
authors: Xia
authors: 0000-0003-4889-2696
authors: X
authors: Guo
authors: Musculoskeletal Research Laboratory, Department of Orthopedics &Traumatology, The Chinese University of Hong Kong, Hong Kong, PR China.
authors: Kaiming
authors: K
authors: Chan
authors: Julius Wolff Institute and Center for Musculoskeletal Surgery, Charité-Universitätsmedizin Berlin, Berlin, Germany.|Berlin-Brandenburg Center for Regenerative Therapies, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors: Frank
authors: 0000-0001-9154-6217
authors: F
authors: Witte
authors: Epithelial Cell Biology Research Centre, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, PR China.
authors: Hsiao Chang
authors: HC
authors: Chan
authors: Department of Materials Science and Engineering, College of Engineering, Peking University, Beijing, PR China.
authors: Yufeng
authors: 0000-0002-7402-9979
authors: Y
authors: Zheng
authors: Musculoskeletal Research Laboratory, Department of Orthopedics &Traumatology, The Chinese University of Hong Kong, Hong Kong, PR China.|Translational Medicine Research &Development Center, Institute of Biomedical and Health Engineering, Shenzhen Institute of Advanced Technology, Shenzhen, PR China.
authors: Ling
authors: L
authors: Qin
mesh_terms: D000818:Animals; D001858:Bone Nails; D015740:Calcitonin Gene-Related Peptide / Q000187:drug effects* / Q000378:metabolism / Q000494:pharmacology; D058286:Calcitonin Receptor-Like Protein / Q000235:genetics; D002211:Capsaicin / Q000633:toxicity; D027682:Cation Transport Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D017362:Cyclic AMP Response Element-Binding Protein / Q000187:drug effects / Q000378:metabolism; D003714:Denervation; D005260:Female; D005264:Femoral Fractures; D005269:Femur / Q000187:drug effects*; D005594:Fracture Fixation, Intramedullary; D017102:Fracture Healing / Q000187:drug effects* / Q000235:genetics; D005727:Ganglia, Spinal / Q000166:cytology; D055879:Gene Knock-In Techniques; D055785:Gene Knockdown Techniques; D006801:Humans; D008274:Magnesium / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects* / Q000235:genetics; D015663:Osteoporosis, Postmenopausal; D058866:Osteoporotic Fractures; D010052:Ovariectomy; D010521:Periosteum / Q000166:cytology; D051381:Rats; D058262:Receptor Activity-Modifying Protein 1 / Q000235:genetics; D018689:Sensory System Agents / Q000633:toxicity; D013234:Stem Cells; D050053:TRPM Cation Channels / Q000378:metabolism; D014157:Transcription Factors / Q000187:drug effects / Q000378:metabolism
chemical_list: C508137:Creb1 protein, rat; D058286:Calcitonin Receptor-Like Protein; C545580:Calcrl protein, rat; D027682:Cation Transport Proteins; D017362:Cyclic AMP Response Element-Binding Protein; C000613456:MagT1 protein, rat; C545508:Ramp1 protein, rat; D058262:Receptor Activity-Modifying Protein 1; D018689:Sensory System Agents; C495181:Sp7 protein, rat; D050053:TRPM Cation Channels; D014157:Transcription Factors; C486584:Trpm7 protein, rat; D008274:Magnesium; D015740:Calcitonin Gene-Related Peptide; D002211:Capsaicin