Implant-derived magnesium induces local neuronal production of CGRP to improve bone-fracture healing in rats
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AbstractOrthopedic 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-alpha (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 Cakrl 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.
All Author(s) ListZhang YF, Xu JK, Ruan YC, Yu MK, O'Laughlin M, Wise H, Chen D, Tian L, Shi DF, Wang JL, Chen SH, Feng JQ, Chow DHK, Xie XH, Zheng LZ, Huang L, Huang S, Leung K, Lu N, Zhao L, Li HF, Zhao DW, Guo X, Chan KM, Witte F, Chan HC, Zheng YF, Qin L
Journal nameNature Medicine
Year2016
Month10
Volume Number22
Issue Number10
PublisherNATURE PUBLISHING GROUP
Pages1160 - 1169
ISSN1078-8956
eISSN1546-170X
LanguagesEnglish-United Kingdom
Web of Science Subject CategoriesBiochemistry & Molecular Biology;Cell Biology;Medicine, Research & Experimental;Biochemistry & Molecular Biology;Cell Biology;Research & Experimental Medicine
