The role of melatonin in the development of postmenopausal osteoporosis

Yang, Keda; Qiu, Xueshan; Cao, Lili; Qiu, Shui

doi:10.3389/fphar.2022.975181

Cited by 8 publications

(3 citation statements)

References 136 publications

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“…22 The role of melatonin in developing postmenopausal osteoporosis has been reported in a recent study. 23 It described a direct effect on bone remodelling by promoting osteogenesis and suppressing osteoclastogenesis, regulating the biological rhythm of bone tissue, attenuating the damage induced by oxidative stress and inflammation on osteoblasts, and preventing osteolysis from reactive oxygen species (ROS) and inflammatory factors. The purpose of the present study was to determine the role of melatonin in the treatment of postmenopausal osteoporosis.…”

Section: Introductionmentioning

confidence: 99%

Melatonin induces RAW264.7 cell apoptosis via the BMAL1/ROS/MAPK-p38 pathway to improve postmenopausal osteoporosis

Wang,

Jiang,

Pan

et al. 2023

Bone Joint Res

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AimsCurrently, the effect of drug treatment for osteoporosis is relatively poor, and the side effects are numerous and serious. Melatonin is a potential drug to improve bone mass in postmenopausal women. Unfortunately, the mechanism by which melatonin improves bone metabolism remains unclear. The aim of this study was to further investigate the potential mechanism of melatonin in the treatment of osteoporosis.MethodsThe effects of melatonin on mitochondrial apoptosis protein, bmal1 gene, and related pathway proteins of RAW264.7 (mouse mononuclear macrophage leukaemia cells) were analyzed by western blot. Cell Counting Kit-8 was used to evaluate the effect of melatonin on cell viability. Flow cytometry was used to evaluate the effect of melatonin on the apoptosis of RAW264.7 cells and mitochondrial membrane potential. A reactive oxygen species (ROS) detection kit was used to evaluate the level of ROS in osteoclast precursors. We used bmal1-small interfering RNAs (siRNAs) to downregulate the Bmal1 gene. We established a postmenopausal mouse model and verified the effect of melatonin on the bone mass of postmenopausal osteoporosis in mice via micro-CT. Bmal1 lentiviral activation particles were used to establish an in vitro model of overexpression of the bmal1 gene.ResultsMelatonin promoted apoptosis of RAW264.7 cells and increased the expression of BMAL1 to inhibit the activation of ROS and phosphorylation of mitogen-activated protein kinase (MAPK)-p38. Silencing the bmal1 gene weakened the above effects of melatonin. After that, we used dehydrocorydaline (DHC) to enhance the activation of MAPK-p38, and the effects of melatonin on reducing ROS levels and promoting apoptosis of RAW264.7 cells were also blocked. Then, we constructed a mouse model of postmenopausal osteoporosis and administered melatonin. The results showed that melatonin improves bone loss in ovariectomized mice. Finally, we established a model of overexpression of the bmal1 gene, and these results suggest that the bmal1 gene can regulate ROS activity and change the level of the MAPK-p38 signalling pathway.ConclusionOur study confirmed that melatonin promotes the apoptosis of RAW264.7 cells through BMAL1/ROS/MAPK-p38, and revealed the therapeutic effect and mechanism of melatonin in postmenopausal osteoporosis. This finding enriches BMAL1 as a potential target for the treatment of osteoporosis and the pathogenesis of postmenopausal osteoporosis.Cite this article: Bone Joint Res 2023;12(11):677–690.

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Section: Introductionmentioning

confidence: 99%

Melatonin induces RAW264.7 cell apoptosis via the BMAL1/ROS/MAPK-p38 pathway to improve postmenopausal osteoporosis

Wang,

Jiang,

Pan

et al. 2023

Bone Joint Res

View full text Add to dashboard Cite

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“…Concerning postmenopausal bone loss, melatonin increases citrate and mineralized nodules in osteoblasts derived from bone marrow mesenchymal stem cells. 22,23 Melatonin is also a promising drug in periodontitis and peri-implantitis treatment. [24][25][26][27][28] This article will briefly discuss the advances made in disclosing and understanding the nature of melatonin activity on bone over the past decade and will center the discussed subject on the effective dose of melatonin as derived from animal studies.…”

Section: Introductionmentioning

confidence: 99%

“…Concerning postmenopausal bone loss, melatonin increases citrate and mineralized nodules in osteoblasts derived from bone marrow mesenchymal stem cells 22,23 . Melatonin is also a promising drug in periodontitis and peri‐implantitis treatment 24–28 .…”

Section: Introductionmentioning

confidence: 99%

Melatonin as a chronobiotic/cytoprotective agent in bone. Doses involved

Cardinali

2023

Journal of Pineal Research

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Because the chronobiotic and cytoprotective molecule melatonin diminishes with age, its involvement in postmenopausal and senescence pathology has been considered since long. One relevant melatonin target site in aging individuals is bone where melatonin chronobiotic effects mediated by MT1 and MT2 receptors are demonstrable. Precursors of bone cells located in bone marrow are exposed to high quantities of melatonin and the possibility arises that melatonin acts a cytoprotective compound via an autacoid effect. Proteins that are incorporated into the bone matrix, like procollagen type I c‐peptide, augment after melatonin exposure. Melatonin augments osteoprotegerin, an osteoblastic protein that inhibits the differentiation of osteoclasts. Osteoclasts are target cells for melatonin as they degrade bone partly by generating free radicals. Osteoclast activity and bone resorption are impaired via the free radical scavenger properties of melatonin. The administration of melatonin in chronobiotic doses (less than 10 mg daily) is commonly used in clinical studies on melatonin effect on bone. However, human equivalent doses allometrically derived from animal studies are in the 1–1.5 mg/kg/day range for a 75 kg human adult, a dose rarely used clinically. In view of the absence of toxicity of melatonin in phase 1 pharmacological studies with doses up to 100 mg in normal volunteers, further investigation is needed to determine whether high melatonin doses have higher therapeutic efficacy in preventing bone loss.

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Exogenous melatonin ameliorates steroid-induced osteonecrosis of the femoral head by modulating ferroptosis through GDF15-mediated signaling

Li,

Zhang

et al. 2023

Stem Cell Res Ther

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Background Ferroptosis is an iron-related form of programmed cell death. Accumulating evidence has identified the pathogenic role of ferroptosis in multiple orthopedic disorders. However, the relationship between ferroptosis and SONFH is still unclear. In addition, despite being a common disease in orthopedics, there is still no effective treatment for SONFH. Therefore, clarifying the pathogenic mechanism of SONFH and investigating pharmacologic inhibitors from approved clinical drugs for SONFH is an effective strategy for clinical translation. Melatonin (MT), an endocrine hormone that has become a popular dietary supplement because of its excellent antioxidation, was supplemented from an external source to treat glucocorticoid-induced damage in this study. Methods Methylprednisolone, a commonly used glucocorticoid in the clinic, was selected to simulate glucocorticoid-induced injury in the current study. Ferroptosis was observed through the detection of ferroptosis-associated genes, lipid peroxidation and mitochondrial function. Bioinformatics analysis was performed to explore the mechanism of SONFH. In addition, a melatonin receptor antagonist and shGDF15 were applied to block the therapeutic effect of MT to further confirm the mechanism. Finally, cell experiments and the SONFH rat model were used to detect the therapeutic effects of MT. Results MT alleviated bone loss in SONFH rats by maintaining BMSC activity through suppression of ferroptosis. The results are further verified by the melatonin MT2 receptor antagonist that can block the therapeutic effects of MT. In addition, bioinformatic analysis and subsequent experiments confirmed that growth differentiation factor 15 (GDF15), a stress response cytokine, was downregulated in the process of SONFH. On the contrary, MT treatment increased the expression of GDF15 in bone marrow mesenchymal stem cells. Lastly, rescue experiments performed with shGDF15 confirmed that GDF15 plays a key role in the therapeutic effects of melatonin. Conclusions We proposed that MT attenuated SONFH by inhibiting ferroptosis through the regulation of GDF15, and supplementation with exogenous MT might be a promising method for the treatment of SONFH. Graphical Abstract

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The role of melatonin in the development of postmenopausal osteoporosis

Cited by 8 publications

References 136 publications

Melatonin induces RAW264.7 cell apoptosis via the BMAL1/ROS/MAPK-p38 pathway to improve postmenopausal osteoporosis

Melatonin induces RAW264.7 cell apoptosis via the BMAL1/ROS/MAPK-p38 pathway to improve postmenopausal osteoporosis

Melatonin as a chronobiotic/cytoprotective agent in bone. Doses involved

Exogenous melatonin ameliorates steroid-induced osteonecrosis of the femoral head by modulating ferroptosis through GDF15-mediated signaling

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