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Melatonin Suppresses Estrogen Deficiency-Induced Osteoporosis and Promotes Osteoblastogenesis by Inactivating the NLRP3 Inflammasome

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Abstract

Postmenopausal osteoporosis induced by estrogen deficiency causes inadequate new bone formation and affects millions of women worldwide. Melatonin can improve bone mineral density at the femoral neck in postmenopausal women with osteopenia. This study aimed to investigate the mechanism of melatonin in estrogen deficiency-induced osteoporosis by focusing on osteoblast differentiation. 12-week-old female C57BL/6J mice were ovariectomized (OVX) and intraperitoneally injected with 10 or 50 mg/kg of melatonin for 8 weeks. Micro-computerized tomography scanning demonstrated that melatonin alleviated OVX-induced bone loss in a dose-dependent manner. Serum levels of ALP and osteocalcin (OCN) were further increased, whereas tartrate-resistant acid phosphatase level was decreased by melatonin in OVX-treated mice. Melatonin promoted osteoblast differentiation in primary bone marrow mesenchymal stem cells from OVX mice. It also inhibited activation of NLRP3 inflammasome in femoral bone protein and in induced osteoblasts stimulated by OVX. Knockdown of NLRP3 attenuated OVX-induced repression of osteogenic differentiation. The NLRP3 inflammasome activator monosodium urate partly abrogated the effect of melatonin on the expression of osteoblastogenic markers, including Runx2 and OCN. Additionally, the results showed that melatonin suppressed NLRP3 inflammasome activation by regulating Wnt/β-catenin signaling, which was confirmed by the Wnt/β-catenin inhibitor recombinant DKK1. These results indicated that melatonin ameliorates estrogen deficiency-induced osteoporosis and impaired osteogenic differentiation potential by suppressing activation of the NLRP3 inflammasome via mediating the Wnt/β-catenin pathway.

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Authors and Affiliations

  1. Department of Endocrinology, The First Affiliated Hospital of Zhengzhou University, Jianshe Road No.1, Erqi District, Zhengzhou, 450052, China

    Lijun Xu, Lixia Zhang, Zhifang Wang, Chong Li, Shan Li, Li Li, Qianying Fan & Lili Zheng

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  1. Lijun Xu
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  2. Lixia Zhang
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Correspondence to Lixia Zhang.

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Lijun Xu, Lixia Zhang, Zhifang Wang, Chong Li, Shan Li, Li Li, Qianying Fan, and Lili Zheng declares that they have no conflict of interest.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

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This study was ethically approved by the Institutional Animal Care and Use Committee of The First Affiliated Hospital of Zhengzhou University and performed in accordance with the criteria defined by the rules of the committee.

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Xu, L., Zhang, L., Wang, Z. et al. Melatonin Suppresses Estrogen Deficiency-Induced Osteoporosis and Promotes Osteoblastogenesis by Inactivating the NLRP3 Inflammasome. Calcif Tissue Int 103, 400–410 (2018). https://doi.org/10.1007/s00223-018-0428-y

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