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

• Published in: Nature medicine Vol. 22; no. 10; pp. 1160 - 1169
• Main Authors: Zhang, Yifeng, Xu, Jiankun, Ruan, Ye Chun, Yu, Mei Kuen, O'Laughlin, Micheal, Wise, Helen, Chen, Di, Tian, Li, Shi, Dufang, Wang, Jiali, Chen, Sihui, Feng, Jian Q, Chow, Dick Ho Kiu, Xie, Xinhui, Zheng, Lizhen, Huang, Le, Huang, Shuo, Leung, Kwoksui, Lu, Na, Zhao, Lan, Li, Huafang, Zhao, Dewei, Guo, Xia, Chan, Kaiming, Witte, Frank, Chan, Hsiao Chang, Zheng, Yufeng, Qin, Ling
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.10.2016
• Subjects: Adenosine triphosphate; Animals; ATP; Biocompatibility; Biodegradability; Biodegradation; Biomedical materials; Bone growth; Bone healing; Bone implants; Bone Nails; Calcitonin; Calcitonin gene-related peptide; Calcitonin Gene-Related Peptide - drug effects; Calcitonin Gene-Related Peptide - metabolism; Calcitonin Gene-Related Peptide - pharmacology; Calcitonin Receptor-Like Protein - genetics; Capsaicin; Capsaicin - toxicity; Cation Transport Proteins - metabolism; Cell Differentiation - drug effects; Cortex (somatosensory); Cortical bone; Cyclic AMP Response Element-Binding Protein - drug effects; Cyclic AMP Response Element-Binding Protein - metabolism; Denervation; Differentiation (biology); Dorsal root ganglia; Female; Femoral Fractures; Femur; Femur - drug effects; Fracture Fixation, Intramedullary; Fracture Healing - drug effects; Fracture Healing - genetics; Fracture repair; Fractures; Ganglia; Ganglia, Spinal - cytology; Gene Knock-In Techniques; Gene Knockdown Techniques; Genes; Genetic aspects; Healing; Health aspects; Humans; Implantation; Ion channels; Magnesium; Magnesium - pharmacology; Nerves; Neurons - drug effects; Neurons - metabolism; Neuropeptides; Orthopedics; Osteogenesis; Osteogenesis - drug effects; Osteogenesis - genetics; Osteoporosis; Osteoporosis, Postmenopausal; Osteoporotic Fractures; Ovariectomy; Periosteum; Periosteum - cytology; Proteins; Rats; Receptor activity modifying proteins; Receptor Activity-Modifying Protein 1 - genetics; Repair; Sensory neurons; Sensory System Agents - toxicity; Stem cell transplantation; Stem Cells; Surgery; Surgical implants; Transcription Factors - drug effects; Transcription Factors - metabolism; Transplants & implants; TRPM Cation Channels - metabolism; Wound healing
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm.4162

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.