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High-purity magnesium pin enhances bone consolidation in distraction osteogenesis via regulating Ptch protein activating Hedgehog-alternative Wnt signaling.

ABSTRACT: Magnesium alloys are promising biomaterials for orthopedic implants because of their degradability, osteogenic effects, and biocompatibility. Magnesium has been proven to promote distraction osteogenesis. However, its mechanism of promoting distraction osteogenesis is not thoroughly studied. In this work, a high-purity magnesium pin developed and applied in rat femur distraction osteogenesis. Mechanical test, radiological and histological analysis suggested that high-purity magnesium pin can promote distraction osteogenesis and shorten the consolidation time. Further RNA sequencing investigation found that alternative Wnt signaling was activated. In further bioinformatics analysis, it was found that the Hedgehog pathway is the upstream signaling pathway of the alternative Wnt pathway. We found that Ptch protein is a potential target of magnesium and verified by molecular dynamics that magnesium ions can bind to Ptch protein. In conclusion, HP Mg implants have the potential to enhance bone consolidation in the DO application, and this process might be via regulating Ptch protein activating Hedgehog-alternative Wnt signaling.

SUBMITTER: Hamushan M

PROVIDER: S-EPMC7691121 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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High-purity magnesium pin enhances bone consolidation in distraction osteogenesis via regulating Ptch protein activating Hedgehog-alternative Wnt signaling.

Hamushan Musha M Cai Weijie W Zhang Yubo Y Ren Zun Z Du Jiafei J Zhang Shaoxiang S Zhao Changli C Cheng Pengfei P Zhang Xiaonong X Shen Hao H Han Pei P

Bioactive materials 20201120 6

Magnesium alloys are promising biomaterials for orthopedic implants because of their degradability, osteogenic effects, and biocompatibility. Magnesium has been proven to promote distraction osteogenesis. However, its mechanism of promoting distraction osteogenesis is not thoroughly studied. In this work, a high-purity magnesium pin developed and applied in rat femur distraction osteogenesis. Mechanical test, radiological and histological analysis suggested that high-purity magnesium pin can pro ...[more]

PMID: 33294734

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Project description:BackgroundDistraction osteogenesis (DO) is a surgical technique to promote bone regeneration which may require long duration for bone consolidation. Bone marrow-derived mesenchymal stem cells (MSCs) have been applied to accelerate bone formation in DO. However, the optimal time point for cell therapy in DO remains unknown. This study sought to determine the optimal time point of cell administration to achieve early bone consolidation in DO. We hypothesized that the ratio of circulating MSCs to peripheral mononuclear cells and the level of cytokines in serum might be indicators for cell administration in DO.MethodsUnilateral tibial osteotomy with an external fixator was performed in adult Sprague Dawley rats. Three days after osteotomy, the tibia was lengthened at 0.5 mm/12 h for 5 days. At first, 5 rats were used to analyze the blood components at 6 different time points (3 days before lengthening, on the day lengthening began, or 3, 6, 10, or 14 days after lengthening began) by sorting circulating MSCs and measuring serum levels of stromal cell-derived factor 1 (SDF-1) and interleukin 1β. Then, 40 rats were used for cell therapy study. A single dose of 5 × 105 allogeneic MSCs was locally injected at the lengthening site on day 3, 6, or 10 after lengthening began, or 3 doses of MSCs were injected at the three time points. Sequential X-ray radiographs were taken weekly. Endpoint examinations included micro-computed tomography analysis, mechanical testing, histomorphometry, and histology.ResultsThe number of circulating MSCs and serum level of SDF-1 were significantly increased during lengthening, and then decreased afterwards. Single injection of MSCs during lengthening phase (on day 3, but not day 6 or 10) significantly increased bone volume fraction, mechanical maximum loading, and bone mineralization of the regenerate. Triple injections of MSCs at three time points also significantly increased bone volume and maximum loading of the regenerates.ConclusionThis study demonstrated that bone consolidation could be accelerated by a single injection of MSCs during lengthening when the ratio of peripheral MSCs to mononuclear cells and the serum SDF-1 presented at peak levels concurrently, suggesting that day 3 after lengthening began may be the optimal time point for cell therapy to promote early bone consolidation.

Project description:Background: Interfragmentary movements have benefits in the improvement of bone formation during distraction osteogenesis (DO). Although several clinical studies reported positive outcomes regarding the application of the cyclic distraction-compression (CDC) dynamization technique in cases with poor bone formation during DO, they are mostly anecdotal without a detailed description. The purpose of this study was to investigate the effectiveness and potential mechanism of different amplitudes and rates of the CDC technique on bone regeneration in a rat femur DO model. Methods: A total of 60 adult male Sprague-Dawley rats underwent right femoral mid-diaphysis transverse osteotomy and were randomly and evenly divided into Control (no manipulation), Group1 (CDC therapy), Group2 (CDC therapy with larger amplitude), and Group3 (CDC therapy with a slower rate) after distraction. The CDC technique was performed during the middle phase of the consolidation period according to different protocols. Animals were sacrificed after 4 and 6 weeks of consolidation. The process of bone formation was monitored by digital radiographs, and the regenerate bone was evaluated by micro-computed tomography (micro-CT), biomechanical test, and histological analysis. The serum contents of hypoxia-inducible factor (HIF)-1α and vascular endothelial growth factor (VEGF) were measured by enzyme-linked immunosorbent assay (ELISA). Results: Bone regeneration after the CDC technique was improved significantly during DO. The digital radiograph, micro-CT, histomorphological analysis, and biomechanical evaluation showed better effects regarding volume, continuity, and mechanical properties of the regenerate bone in Group2 and Group3 when compared to Group1. The angiogenic and osteogenic markers were more highly expressed in Group2 and Group3 than in Group1 according to the immunohistochemical analysis. As for ELISA, the serum contents of HIF-1α and VEGF were also increased after the CDC technique, especially in Group2 and Group3. Conclusion: The CDC dynamization technique has benefits on the improvement of bone formation during DO, and the mechanism may be due to tissue hypoxia activating the HIF pathway followed by the augmentation of osteogenic-angiogenic coupling. Better outcomes may be achieved by moderately increasing the amplitude and slowing down the rate of the CDC technique.

Dataset Information

High-purity magnesium pin enhances bone consolidation in distraction osteogenesis via regulating Ptch protein activating Hedgehog-alternative Wnt signaling.

Publications

High-purity magnesium pin enhances bone consolidation in distraction osteogenesis via regulating Ptch protein activating Hedgehog-alternative Wnt signaling.

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