☆ 4.8 Article

Biodegradable magnesium combined with distraction osteogenesis synergistically stimulates bone tissue regeneration via CGRP-FAK-VEGF signaling axis

BIOMATERIALS (2021)

Journal

BIOMATERIALS

Volume 275, Issue -, Pages -

Publisher

ELSEVIER SCI LTD

DOI: 10.1016/j.biomaterials.2021.120984

Keywords

Magnesium; Distraction osteogenesis; Calcitonin gene-related peptide; Focal adhesion kinase; Vascular endothelial growth factor

Funding

Hong Kong RGC General Research Fund 2016/2017 [14140816]
RGC Theme-based Research Scheme [T13402/17N]
RGC Collaborative Research Fund [C4026-17WF]
Innovation and Technology Commission Funding [ITS/208/18FX]
Shenzhen-HK Collaborative Zone project [HZQBKCZYB20200089]
Key-Area Research and Development Program of Guang-dong Province [2019B010941001]
National Natural Science Foun-dation of China [81802152]

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Abstract

This study demonstrated the mechanisms of magnesium nail implantation in promoting critical size bone defect repair, showing that the CGRP-FAK-VEGF signaling axis could accelerate new bone and vessel formation, enhancing the therapeutic effect.

Critical size bone defects are frequently caused by accidental trauma, oncologic surgery, and infection. Distraction osteogenesis (DO) is a useful technique to promote the repair of critical size bone defects. However, DO is usually a lengthy treatment, therefore accompanied with increased risks of complications such as infections and delayed union. Here, we demonstrated that magnesium (Mg) nail implantation into the marrow cavity degraded gradually accompanied with about 4-fold increase of new bone formation and over 5-fold of new vessel formation as compared with DO alone group in the 5 mm femoral segmental defect rat model at 2 weeks after distraction. Mg nail upregulated the expression of calcitonin gene-related peptide (CGRP) in the new bone as compared with the DO alone group. We further revealed that blockade of the sensory nerve by overdose capsaicin blunted Mg nail enhanced critical size bone defect repair during the DO process. CGRP concentrationdependently promoted endothelial cell migration and tube formation. Meanwhile, CGRP promoted the phosphorylation of focal adhesion kinase (FAK) at Y397 site and elevated the expression of vascular endothelial growth factor A (VEGFA). Moreover, inhibitor/antagonist of CGRP receptor, FAK, and VEGF receptor blocked the Mg nail stimulated vessel and bone formation. We revealed, for the first time, a CGRP-FAK-VEGF signaling axis linking sensory nerve and endothelial cells, which may be the main mechanism underlying Mg-enhanced critical size bone defect repair when combined with DO, suggesting a great potential of Mg implants in reducing DO treatment time for clinical applications.

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CGRP-modulated M2 macrophages regulate osteogenesis of MC3T3-E1 via Yap1

Qin Zhang, Bingfeng Wu, Ying Yuan, Xinyuan Zhang, Yanjun Guo, Ping Gong, Lin Xiang

Summary: The study suggests that CGRP may play a critical role in bone healing by modulating the biological function of M2 macrophages and influencing osteogenesis. Results indicate that CGRP can affect the secretion of osteogenic factors and have multiple effects on MC3T3 osteogenesis through regulating the osteoimmune environment.

ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS (2021)