Implant-derived magnesium induces local neuronal production of CGRP to improve bone-fracture healing in rats
Open accessAbstract
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.
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Biodegradable Mg alloys offer bone-matched mechanical properties, osteoimmunomodulation via Mg2+/H2 release, and inherent antibacterial effects from degradation products or alloying elements.
“Biodegradable Mg alloys have emerged as potent alternatives for treating IBDs [5,6], offering bone-matched mechanical properties, osteoimmunomodulation via Mg2+/H2 release, and inherent antibacterial effects from degradation products or alloying elements (e.g., Zn, Ag, Cu) [[5], [6], [7], [8]].”
From Nanocatalytic magnesium osteoimplants with biodegradable self-adaptive interfaces for therapeutic repair of infected bone defects (2026) · cites this paper as [7]
The Abstract (page not provided) describes magnesium as biodegradable and having mechanical properties similar to natural bone. It does not attribute osteoimmunomodulation to Mg2+ or H2 release, or describe antibacterial effects from degradation products or Zn, Ag, or Cu. Its mention of infections concerns complications of implant-removal surgery, not antibacterial activity. (LLM, conf=0.88)
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Self-citation
- Authors
- Zhang, Y., Xu, J., Ruan, Y. C., Yu, M. K., O'Laughlin, M., Wise, H., Chen, D., Tian, L., Shi, D., Wang, J., Chen, S., Feng, J. Q., Chow, D. H. K., Xie, X., Zheng, L., Huang, L., Huang, S., Leung, K., Lu, N., Zhao, L., Li, H., Zhao, D., Guo, X., Chan, K., Witte, F., Chan, H. C., Zheng, Y., & Qin, L.
- Affiliations
- Chinese University of Hong Kong (HK)
- Rush University (US)
- Texas A&M Health Science Center (US)
- Dalian University (CN)
- Hong Kong Polytechnic University (HK)
- Stiftung Charité (DE)
- Peking University (CN)
- Corresponding author
- Zheng, Yufeng
- Qin, Ling
- ORCID
- Venue
- Nature Medicine
- Published
- 2016-08-29
- Volume
- 22
- Issue
- 10
- Pages
- 1160-1169
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC5293535
- OpenAlex
- W2510993966
- Cited by
- 1,051
- References
- 69
- Citations by year
- 2026: 96 · 2025: 158 · 2024: 151 · 2023: 119 · 2022: 141 · 2021: 108 · 2020: 98 · 2019: 67 · 2018: 65 · 2017: 42 · 2016: 6
- FWCI
- 56.21
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- PolyU Institutional Research Archive (Hong Kong Polytechnic University) (submittedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Funders
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R21AR067935, R01AR062136, R01AR054465)
- Topics
- Health Sciences › Medicine › Epidemiology › Bone fractures and treatments
- Physical Sciences › Engineering › Biomedical Engineering › Bone Tissue Engineering Materials
- Health Sciences › Nursing › Nutrition and Dietetics › Magnesium in Health and Disease
- Keywords
- magnesium, fracture healing, calcitonin gene-related peptide, CGRP receptor, dorsal root ganglia, periosteum, bone formation, intramedullary pin, ovariectomy-induced osteoporosis, periosteal stem cells, osteogenic differentiation, TRPM7, MAGT1, ATP, synaptic vesicles, CREB1, Osterix, sensory nerves
- MeSH terms
- Animals, Bone Nails, Capsaicin, Cell Differentiation, Denervation, Female, Femoral Fractures, Femur, Fracture Fixation, Intramedullary, Ganglia, Spinal, Humans, Magnesium, Neurons, Osteogenesis, Ovariectomy, Periosteum, Stem Cells, Transcription Factors, Osteoporosis, Postmenopausal, Calcitonin Gene-Related Peptide, Fracture Healing, Cyclic AMP Response Element-Binding Protein, Sensory System Agents, Cation Transport Proteins, TRPM Cation Channels, Rats, Gene Knockdown Techniques, Gene Knock-In Techniques, Receptor Activity-Modifying Protein 1, Calcitonin Receptor-Like Protein, Osteoporotic Fractures
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