Implant-derived magnesium induces local neuronal production of CGRP to improve bone-fracture healing in rats
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摘要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-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.
著者Zhang 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
期刊名稱Nature Medicine
出版年份2016
月份10
卷號22
期次10
出版社NATURE PUBLISHING GROUP
頁次1160 - 1169
國際標準期刊號1078-8956
電子國際標準期刊號1546-170X
語言英式英語
Web of Science 學科類別Biochemistry & Molecular Biology;Cell Biology;Medicine, Research & Experimental;Biochemistry & Molecular Biology;Cell Biology;Research & Experimental Medicine

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