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. Epub 2016 Aug 29.

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.

MeSH terms

  • Animals
  • Bone Nails*
  • Calcitonin Gene-Related Peptide / drug effects*
  • Calcitonin Gene-Related Peptide / metabolism
  • Calcitonin Gene-Related Peptide / pharmacology
  • Calcitonin Receptor-Like Protein / genetics
  • Capsaicin / toxicity
  • Cation Transport Proteins / metabolism
  • Cell Differentiation / drug effects
  • Cyclic AMP Response Element-Binding Protein / drug effects
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Denervation
  • Female
  • Femoral Fractures
  • Femur / drug effects*
  • Fracture Fixation, Intramedullary
  • Fracture Healing / drug effects*
  • Fracture Healing / genetics
  • Ganglia, Spinal / cytology
  • Gene Knock-In Techniques
  • Gene Knockdown Techniques
  • Humans
  • Magnesium / pharmacology*
  • Neurons / drug effects*
  • Neurons / metabolism
  • Osteogenesis / drug effects*
  • Osteogenesis / genetics
  • Osteoporosis, Postmenopausal
  • Osteoporotic Fractures
  • Ovariectomy
  • Periosteum / cytology
  • Rats
  • Receptor Activity-Modifying Protein 1 / genetics
  • Sensory System Agents / toxicity
  • Stem Cells
  • TRPM Cation Channels / metabolism
  • Transcription Factors / drug effects
  • Transcription Factors / metabolism

Substances

  • CREB1 protein, rat
  • Calcitonin Receptor-Like Protein
  • Calcrl protein, rat
  • Cation Transport Proteins
  • Cyclic AMP Response Element-Binding Protein
  • MagT1 protein, rat
  • Ramp1 protein, rat
  • Receptor Activity-Modifying Protein 1
  • Sensory System Agents
  • Sp7 protein, rat
  • TRPM Cation Channels
  • Transcription Factors
  • Trpm7 protein, rat
  • Magnesium
  • Calcitonin Gene-Related Peptide
  • Capsaicin