Melatonin Accelerates Osteoporotic Bone Defect Repair by Promoting Osteogenesis–Angiogenesis Coupling

Zheng, Shusen; Zhou, Chun-Hao; Yang, Han; Li, Junhua; Feng, Ziyu; Liao, Liqiong; Li, Yikai

doi:10.3389/fendo.2022.826660

Cited by 33 publications

(14 citation statements)

References 60 publications

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“…Platelet‐derived growth factor‐BB has been identified as a potential inducer of angiogenesis in CD31 + and Emcn + endothelial cells 39 . While melatonin alone did not directly stimulate angiogenic differentiation in human umbilical vein endothelial cells, the upregulation of vascular endothelial growth factor in BMMSCs facilitated capillary formation and expedited the repair of osteoporotic bone defects 40 . Henceforth, a comprehensive examination of the impact of melatonin on the coupling of osteogenesis and angiogenesis, along with its underlying mechanisms, will be conducted in our forthcoming research.…”

Section: Discussionmentioning

confidence: 99%

Melatonin rescues the mitochondrial function of bone marrow‐derived mesenchymal stem cells and improves the repair of osteoporotic bone defect in ovariectomized rats

Gu,

Zhou,

et al. 2023

Journal of Pineal Research

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Osteoporotic bone defects, a severe complication of osteoporosis, are distinguished by a delayed bone healing process and poor repair quality. While bone marrow‐derived mesenchymal stem cells (BMMSCs) are the primary origin of bone‐forming osteoblasts, their mitochondrial function is impaired, leading to inadequate bone regeneration in osteoporotic patients. Melatonin is well‐known for its antioxidant properties and regulation on bone metabolism. The present study postulated that melatonin has the potential to enhance the repair of osteoporotic bone defects by restoring the mitochondrial function of BMMSCs. In vitro administration of melatonin at varying concentrations (0.01, 1, and 100 μM) demonstrated a significant dose‐dependent improvement in the mitochondrial function of BMMSCs obtained from ovariectomized rats (OVX‐BMMSCs), as indicated by an elevation in mitochondrial membrane potential, adenosine triphosphate synthesis and expression of mitochondrial respiratory chain factors. Melatonin reduced the level of mitochondrial superoxide by activating the silent information regulator type 1 (SIRT1) and its downstream antioxidant enzymes, particularly superoxide dismutase 2 (SOD2). The protective effects of melatonin were found to be nullified upon silencing of Sirt1 or Sod2, underscoring the crucial role of the SIRT1‐SOD2 axis in the melatonin‐induced enhancement of mitochondrial energy metabolism in OVX‐BMMSCs. To achieve a sustained and localized release of melatonin, silk fibroin scaffolds loaded with melatonin (SF@MT) were fabricated. The study involved the surgical creation of bilateral femur defects in OVX rats, followed by the implantation of SF@MT scaffolds. The results indicated that the application of melatonin partially restored the mitochondrial energy metabolism and osteogenic differentiation of OVX‐BMMSCs by reinstating mitochondrial redox homeostasis. These findings suggest that the localized administration of melatonin through bone implants holds potential as a therapeutic approach for addressing osteoporotic bone defects.

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Section: Discussionmentioning

confidence: 99%

Melatonin rescues the mitochondrial function of bone marrow‐derived mesenchymal stem cells and improves the repair of osteoporotic bone defect in ovariectomized rats

Gu,

Zhou,

et al. 2023

Journal of Pineal Research

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“…However, the repair of fractures can be prolonged in various underlying diseases, such as diabetes ( Chen et al, 2022b ), vascular diseases ( Liu et al, 2022 ), and autoimmune diseases ( Tian et al, 2022 ). These diseases often affect bone repair by altering blood vessel formation, including microvascular regeneration ( Zheng et al, 2022 ). In this study, TBX3 functions as a TF that regulates VEGF expression and has a positive effect on skeletal microvascular regeneration by regulating osteoblasts.…”

Section: Discussionmentioning

confidence: 99%

TBX3 regulates the transcription of VEGFA to promote osteoblasts proliferation and microvascular regeneration

Yang

et al. 2022

PeerJ

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Objective Osteochondral decellularization can promote local vascular regeneration, but the exact mechanism is unknown. The aim of this study is to study osteogenic microvascular regeneration in single cells. Methods The scRNA-seq dataset of human periosteal-derived cells (hPDCs) were analyzed by pySCENIC. To examine the role of TBX3 in osteogenesis and vascularization, cell transfection, qRT-PCR, western blot, and CCK-8 cell proliferation assays were performed. Results TCF7L2, TBX3, FLI1, NFKB2, and EZH2 were found to be transcription factors (TFs) most closely associated with corresponding cells. The regulatory network of these TFs was then visualized. Our study knocked down the expression of TBX3 in human osteoblast cell lines. In the TBX3 knockdown group, we observed decreased expression of VEGFA, VEGFB, and VEGFC. Moreover, Western blot analysis showed that downregulating TBX3 resulted in a reduction of VEGFA expression. And TBX3 stimulated osteoblast proliferation in CCK-8 assays. Conclusion TBX3 regulates VEGFA expression and promotes osteoblast proliferation in skeletal microvasculature formation. The findings provide a theoretical basis for investigating the role of TBX3 in promoting local vascular regeneration.

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“…Application of MLT has recently been found to be related with enhancement of osteogenesis and abolishment of osteoclast formation [ 87 ]. Moreover, MLT is able to induce osteogenesis coupled with angiogenesis in rat BMMSCs when cultured in osteogenic medium [ 88 ]. MLT can restore osteogenic differentiation of human BMMSCs undergone oxidative stress by hydrogen peroxide through activation of AMPK signaling pathway.…”

Section: Small Moleculesmentioning

confidence: 99%

Recent advances on small molecules in osteogenic differentiation of stem cells and the underlying signaling pathways

et al. 2022

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Bone-related diseases are major contributors to morbidity and mortality in elderly people and the current treatments result in insufficient healing and several complications. One of the promising areas of research for healing bone fractures and skeletal defects is regenerative medicine using stem cells. Differentiating stem cells using agents that shift cell development towards the preferred lineage requires activation of certain intracellular signaling pathways, many of which are known to induce osteogenesis during embryological stages. Imitating embryological bone formation through activation of these signaling pathways has been the focus of many osteogenic studies. Activation of osteogenic signaling can be done by using small molecules. Several of these agents, e.g., statins, metformin, adenosine, and dexamethasone have other clinical uses but have also shown osteogenic capacities. On the other hand, some other molecules such as T63 and tetrahydroquinolines are not as well recognized in the clinic. Osteogenic small molecules exert their effects through the activation of signaling pathways known to be related to osteogenesis. These pathways include more well-known pathways including BMP/Smad, Wnt, and Hedgehog as well as ancillary pathways including estrogen signaling and neuropeptide signaling. In this paper, we review the recent data on small molecule-mediated osteogenic differentiation, possible adjunctive agents with these molecules, and the signaling pathways through which each small molecule exerts its effects. Graphical Abstract

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Melatonin Accelerates Osteoporotic Bone Defect Repair by Promoting Osteogenesis–Angiogenesis Coupling

Cited by 33 publications

References 60 publications

Melatonin rescues the mitochondrial function of bone marrow‐derived mesenchymal stem cells and improves the repair of osteoporotic bone defect in ovariectomized rats

Melatonin rescues the mitochondrial function of bone marrow‐derived mesenchymal stem cells and improves the repair of osteoporotic bone defect in ovariectomized rats

TBX3 regulates the transcription of VEGFA to promote osteoblasts proliferation and microvascular regeneration

Recent advances on small molecules in osteogenic differentiation of stem cells and the underlying signaling pathways

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