The Adenosine A2A Receptor Agonist Accelerates Bone Healing and Adjusts Treg/Th17 Cell Balance through Interleukin 6

Zheng, Xi; Wang, Dong

doi:10.1155/2020/2603873

Cited by 18 publications

(26 citation statements)

References 50 publications

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“…PASS 11.0 software was used to calculate the sample size. We referred to the previous literature by using burning periosteum to make bone nonunion rat model and all of them were successful [ 11 , 15 , 16 ]. In addition, there was no report about making model failure.…”

Section: Methodsmentioning

confidence: 99%

Development of a tibial experimental non-union model in rats

Wang

Liu

et al. 2021

J Orthop Surg Res

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Background Many non-union animal models have been developed to explore the problems surrounding fracture healing. However, the existing models are not perfect and cannot satisfy all non-union studies. This study aimed to make a non-union model of the tibia in rats by cauterization of the posterior of 2 mm on both sides of the fracture end after open osteotomy of the tibia and fixing the fractured tibia with a Kirschner wire 0.8 mm in diameter. Methods For this study, 96 female adult Sprague-Dawley (SD) rats were used. The rats underwent surgery to produce a tibial open fracture and were fixed with a 0.8-mm diameter Kirschner wire. In 48 of the rats, the periosteum proximal and distal to the fracture end was cauterized. Results At 2, 4, 6, and 8 weeks after surgery, radiological and histological analysis showed typical physiological healing in the control group, and the healing rate was 100% at 6 weeks. But the non-union group was characterized by resorption of the fracture ends with few callus formations and no bridging callus formation, and the healing rate was 0% at 8 weeks. Conclusions This method represents a reproducible model to create atrophic non-unions. This model provides a new option for studying the basic healing mechanisms and evaluating new therapies for bone regeneration and treatment of non-unions.

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Section: Methodsmentioning

confidence: 99%

Development of a tibial experimental non-union model in rats

Wang

Liu

et al. 2021

J Orthop Surg Res

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“…For the in vivo experiments, the tibia fracture nonunion model was used and the sample size was estimated by referring to previous studies on the ADA2AR promotion of fracture healing, because there have been no studies of how the ADA2AR accelerates angiogenesis in bone healing. 2,26 The study showed that the ADA2AR promoted bone healing (the rate of increase was 100%) and the fracture healing rate of the control group was 0 at 8 weeks. 2,26 In addition, α was set as 0.05 (two-sided), the failure rate of the model was 10%, and 1-β was set as 0.80.…”

Section: Animal Sample Sizementioning

confidence: 96%

“…Bone fracture is a common cause of disability and the nonunion rate is approximately 5-10% despite patients receiving active treatment. [1][2][3] Poor vascularization leads to nonunion, and vascular endothelial cells (VECs) are known to be critical to nonunion. [3][4][5][6] Damaged VECs release many bioactive factors, which accelerate VEC proliferation and migration during the initial process of angiogenesis after bone fracture.…”

Section: Introductionmentioning

confidence: 99%

“…The adenosine A2A receptor (ADA2AR), a member of the G-protein coupled receptor family, is an immunosuppressive and anti-inflammatory molecule. 2,13,14 There have been no studies on the role of the ADA2AR in angiogenesis during bone healing and the effects of ADA2AR on VECs are still under debate. [15][16][17][18][19][20][21][22][23] Desai et al [20][21][22] proposed that ADA2AR agonists could promote vascular tube formation in vitro, but some studies found that adenosine A1 or A2B receptor agonists were the receptor subtypes of adenosine that promoted VEC proliferation or angiogenesis.…”

Section: Introductionmentioning

confidence: 99%

“…In 2020, we proposed that CGS21680 could promote fracture healing. 2 However, the role of the ADA2AR in angiogenesis and its effects on VECs in the bone fracture microenvironment have not been discussed.…”

Section: Introductionmentioning

confidence: 99%

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The Role of Adenosine Receptor A2A in the Regulation of Macrophage Exosomes and Vascular Endothelial Cells During Bone Healing

Wang¹,

Wang²,

Zhou³

et al. 2021

JIR

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Background: Macrophage exosomes and vascular endothelial cells (VECs) are critical to bone healing. However, few studies explore the molecular regulation of them in the bone fracture microenvironment. Methods: In this study, we explored the effects of adenosine receptor A2A (ADA2AR) in macrophage exosomes and VECs during bone healing. CGS21680 (an ADA2AR agonist) and ZM241385 (an ADA2AR antagonist) were used. First, the effects of the ADA2AR on VECs during bone healing were studied in vivo in a rat tibial fracture model. Second, the effects of ADA2AR on VECs and in the regulation of VECs by macrophages were examined in the bone fracture microenvironment. Third, the effects of ADA2AR on the regulation of macrophage exosomes on VECs were analyzed. Finally, the genes and long non-coding RNAs (lncRNAs) associated with the regulation of VECs by the ADA2AR were examined by high-throughput sequencing and bioinformatics analysis. Results: CGS21680 accelerated VEC proliferation in the early stage of bone healing and that ZM241385 suppressed VEC proliferation in vivo. ZM241385 inhibited cell viability and tube formation in vitro. However, CGS21680 did not promote tube formation, cell proliferation, or cell migration in vitro. The inhibition of macrophage exosomes could suppress tube formation and VEC migration. CGS21680 had no effects on tube formation in a macrophage-VEC co-culture. The macrophage exosomes were purified and CGS21680 promoted the macrophage secretion of exosomes. In contrast, ZM241385 inhibited the macrophage secretion exosomes. Finally, the lncRNA and mRNA involved in the activation of the ADA2AR in VECs were analyzed. CGS21680 upregulated 3274 mRNAs and downregulated 2236 mRNAs, and upregulated 1696 lncRNAs and downregulated 1882 lncRNAs. The hub genes involved in angiogenesis were Flt1, Fgf2, Mapk14, Fn1, and Jun. Conclusion:The activation of ADA2AR was essential for angiogenesis and the secretion of exosomes by macrophages during bone healing; moreover, the inactivation of the ADA2AR led to poor angiogenesis and bone nonunion.

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Osteoimmunology of Fracture Healing

Molitoris,

Huang,

Baht

2024

Curr Osteoporos Rep

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Purpose of Review The purpose of this review is to summarize what is known in the literature about the role inflammation plays during bone fracture healing. Bone fracture healing progresses through four distinct yet overlapping phases: formation of the hematoma, development of the cartilaginous callus, development of the bony callus, and finally remodeling of the fracture callus. Throughout this process, inflammation plays a critical role in robust bone fracture healing. Recent Findings At the onset of injury, vessel and matrix disruption lead to the generation of an inflammatory response: inflammatory cells are recruited to the injury site where they differentiate, activate, and/or polarize to secrete cytokines for the purposes of cell signaling and cell recruitment. This process is altered by age and by sex. Summary Bone fracture healing is heavily influenced by the presence of inflammatory cells and cytokines within the healing tissue. Graphical Abstract

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The Adenosine A2A Receptor Agonist Accelerates Bone Healing and Adjusts Treg/Th17 Cell Balance through Interleukin 6

Cited by 18 publications

References 50 publications

Development of a tibial experimental non-union model in rats

Development of a tibial experimental non-union model in rats

The Role of Adenosine Receptor A2A in the Regulation of Macrophage Exosomes and Vascular Endothelial Cells During Bone Healing

Osteoimmunology of Fracture Healing

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