Calcitonin Gene-Related Peptide Enhances Distraction Osteogenesis by Increasing Angiogenesis

Mi, Jie; Xu, Jiankun; Yao, Hao; Li, Xisheng; Tong, Wenxue; Li, Ye; Dai, Bingyang; He, Xuan; Chow, Dick Ho Kiu; Li, Gang; Lui, Kathy O.; Zhao, Jie; Qin, Ling

doi:10.1089/ten.tea.2020.0009

Cited by 58 publications

(42 citation statements)

References 65 publications

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“…Apart from applying angiogenic and osteogenic factors to accelerate bone formation in DO, other factors such as NGFβ had also been applied to shorten the consolidation phase in DO [ 56 ]. The local injection of neuropeptide CGRP accelerated DO bone formation via the enhancement of angiogenesis [ 57 ]. Despite many beneficial results of growth factor therapies, their application in clinical practice is limited by high expense, short biologic half-life, and the lack of efficient delivery methods [ 48 , 50 ].…”

Section: Biological Agentsmentioning

confidence: 99%

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Overview of methods for enhancing bone regeneration in distraction osteogenesis: Potential roles of biometals

Pan

et al. 2021

Journal of Orthopaedic Translation

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Background Distraction osteogenesis (DO) is a functional tissue engineering approach that applies gradual mechanical traction on the bone tissues after osteotomy to stimulate bone regeneration. However, DO still has disadvantages that limit its clinical use, including long treatment duration Methods Review the current methods of promoting bone formation and consolidation in DO with particular interest on biometal. Results Numerous approaches, including physical therapy, gene therapy, growth factor-based therapy, stem-cell-based therapy, and improved distraction devices, have been explored to reduce the DO treatment duration with some success. Nevertheless, no approach to date is widely accepted in clinical practice due to various reasons, such as high expense, short biologic half-life, and lack of effective delivery methods. Biometals, including calcium (Ca), magnesium (Mg), zinc (Zn), copper (Cu), manganese (Mn), and cobalt (Co) have attracted attention in bone regeneration attributed to their biodegradability and bioactive components released during in vivo degradation. Conclusion This review summarizes the current therapies accelerating bone formation in DO and the beneficial role of biometals in bone regeneration, particularly focusing on the use of biometal Mg and its alloy in promoting bone formation in DO. Translational potential: The potential clinical applications using Mg-based devices to accelerate DO are promising. Mg stimulates expression of multiple intrinsic biological factors and the development of Mg as an implantable component in DO may be used to argument bone formation and consolidation in DO.

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Section: Biological Agentsmentioning

confidence: 99%

“…CGRP can also promote angiogenesis by promoting endothelial cell migration and tube formation [ 122 ]. Moreover, CGRP has been reported to promote bone formation via enhancing angiogenesis during DO [ 57 ]. The pro-angiogenic effect of Mg may be attributable to CGRP-mediated signaling.…”

Section: Advantages and Disadvantages Of Mg In Bone Regenerationmentioning

confidence: 99%

Overview of methods for enhancing bone regeneration in distraction osteogenesis: Potential roles of biometals

Pan

et al. 2021

Journal of Orthopaedic Translation

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“…In addition, the pharmacological effects of the calcitonin family peptides on osteogenesis and angiogenesis have also been widely investigated. For instance, ADM2 was reported to directly improve the angiogenic activity of endothelial cells (Wang et al, 2018), and CGRP, which shares CLR/RAMP1 as a common receptor with ADM2 (Naot et al, 2019), could improve osteogenesis and angiogenesis through the Wnt (Zhou et al, 2016) and AKT (Mi et al, 2021) pathways, respectively. Meanwhile, ADM also possesses similar angiogenesis-promoting functions as ADM2 , although the additional activities of ADM on improving osteogenesis (Cornish et al, 2001) may not be mediated by its common receptors with ADM2, since CLR/RAMP1 is not one of the receptors ADM prefers to combine with and there is no expression of CLR/RAMP3 in BMSCs and osteoblasts (Naot and Cornish, 2008).…”

Section: Discussionmentioning

confidence: 99%

“…Meanwhile, most peptides in the calcitonin family possess similar biological activities, and the pharmacological effects of CGRP and ADM, which share the dimers of calcitonin receptor-like receptor (CLR) and receptormodifying proteins (RAMPs) as common receptors, especially CLR/RAMP1 and CLR/RAMP3, with ADM2, are the most similar to those of ADM2 (Naot et al, 2019). Therefore, previous investigations of CGRP and ADM have been of great significance for studying ADM2 in the areas of osteogenesis, angiogenesis, and bone regeneration (Cornish et al, 2001;Zhou et al, 2016;Mi et al, 2021), in which the biological functions of ADM2 have rarely been investigated. Of note, the most reported biological functions of ADM2 are mediated through the intracellular activation of protein kinase B (AKT) and the inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) (Song et al, 2009;Teng et al, 2011;Li et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Accelerated Bone Regeneration by Adrenomedullin 2 Through Improving the Coupling of Osteogenesis and Angiogenesis via β-Catenin Signaling

Wang

Kong

et al. 2021

Front. Cell Dev. Biol.

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Both osteogenic differentiation and the pro-angiogenic potential of bone marrow mesenchymal stem cells (BMSCs) contribute to bone regeneration during distraction osteogenesis (DO). Adrenomedullin 2 (ADM2), an endogenous bioactive peptide belonging to the calcitonin gene-related peptide family, exhibits various biological activities associated with the inhibition of inflammation and the attenuation of ischemic-hypoxic injury. However, the effects and underlying mechanisms of ADM2 in osteogenic differentiation and the pro-angiogenic potential of BMSCs, along with bone regeneration, remain poorly understood. In the present study, we found that osteogenic induction enhanced the pro-angiogenic potential of BMSCs, and ADM2 treatment further improved the osteogenic differentiation and pro-angiogenic potential of BMSCs. Moreover, the accumulation and activation of β-catenin, which is mediated by the inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and the activation of protein kinase B (AKT), have been shown to contribute to the effects of ADM2 on BMSCs. In vivo, ADM2 accelerated vessel expansion and bone regeneration, as revealed by improved radiological and histological manifestations and the biomechanical parameters in a rat DO model. Based on the present results, we concluded that ADM2 accelerates bone regeneration during DO by enhancing the osteogenic differentiation and pro-angiogenic potential of BMSCs, partly through the NF-κB/β-catenin and AKT/β-catenin pathways. Moreover, these findings imply that BMSC-mediated coupling of osteogenesis and angiogenesis may be a promising therapeutic strategy for DO patients.

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“…Embryonic stem cells express VE-cadherin (CD144) during endothelial differentiation [31]. Neuropeptide (CGRP) can significantly increase the fraction of CD31 + CD144 + EPCs, and the capillary density in the bone defect at the end of the distraction phase [32]. Therefore, we proposed that α7nAChR + Sca1 + cells expressing VEcadherin might be EPCs.…”

Section: Introductionmentioning

confidence: 99%

Vagal α7nAChR signaling regulates α7nAChR+Sca1+ cells during lung injury repair

Chen

Song

et al. 2020

Stem Cell Res Ther

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Background: The distal airways of the lung and bone marrow are innervated by the vagus nerve. Vagal α7nAChR signaling plays a key role in regulating lung infection and inflammation; however, whether this pathway regulates α7nAChR + Sca1 + cells during lung injury repair remains unknown. We hypothesized that vagal α7nAChR signaling controls α7nAChR + Sca1 + cells, which contribute to the resolution of lung injury. Methods: Pneumonia was induced by intratracheal challenge with E. coli. The bone marrow mononuclear cells (BM-MNCs) were isolated from the bone marrow of pneumonia mice for immunofluorescence. The bone marrow, blood, BAL, and lung cells were isolated for flow cytometric analysis by labeling with anti-Sca1, VE-cadherin, p-Akt1, or Flk1 antibodies. Immunofluorescence was also used to examine the coexpression of α7nAChR, VE-cadherin, and p-Akt1. Sham, vagotomized, α7nAChR knockout, and Akt1 knockout mice were infected with E. coli to study the regulatory role of vagal α7nAChR signaling and Akt1 in Sca1 + cells. Results: During pneumonia, BM-MNCs were enriched with α7nAChR + Sca1 + cells, and this cell population proliferated. Transplantation of pneumonia BM-MNCs could mitigate lung injury and increase engraftment in recipient pneumonia lungs. Activation of α7nAChR by its agonist could boost α7nAChR + Sca1 + cells in the bone marrow, peripheral blood, and bronchoalveolar lavage (BAL) in pneumonia. Immunofluorescence revealed that α7nAChR, VE-cadherin, and p-Akt1 were coexpressed in the bone marrow cells. Vagotomy could reduce α7nAChR + VE-cadherin + and VE-cadherin + p-Akt1 + cells in the bone marrow in pneumonia. Knockout of α7nAChR reduced VE-cadherin + cells and p-Akt1 + cells in the bone marrow. Deletion of Akt1 reduced Sca1 + cells in the bone marrow and BAL. More importantly, 91.3 ± 4.9% bone marrow and 77.8 ± 4.9% lung α7nAChR + Sca1 + VE-cadherin + cells expressed Flk1, which is a key marker of endothelial progenitor cells (EPCs). Vagotomy reduced α7nAChR + Sca1 + VE-cadherin + p-Akt1 + cells in the bone marrow and lung from pneumonia mice. Treatment with cultured EPCs reduced ELW compared to PBS treatment in E. coli pneumonia mice at 48 h. The ELW was further reduced by treatment with EPCs combining with α7nAChR agonist-PHA568487 compared to EPC treatments only.

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Calcitonin Gene-Related Peptide Enhances Distraction Osteogenesis by Increasing Angiogenesis

Cited by 58 publications

References 65 publications

Overview of methods for enhancing bone regeneration in distraction osteogenesis: Potential roles of biometals

Overview of methods for enhancing bone regeneration in distraction osteogenesis: Potential roles of biometals

Accelerated Bone Regeneration by Adrenomedullin 2 Through Improving the Coupling of Osteogenesis and Angiogenesis via β-Catenin Signaling

Vagal α7nAChR signaling regulates α7nAChR+Sca1+ cells during lung injury repair

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