Melatonin attenuates titanium particle-induced osteolysis via activation of Wnt/β-catenin signaling pathway

Ping, Zichuan; Hu, Xuanyang; Wang, Liangliang; Shi, Jiawei; Tao, Yunxia; Wu, Xiexing; Hou, Zhenyang; Guo, Xiaobin; Wen, Zhang; Yang, Huilin; Xu, Yaozeng; Wang, Zhirong; Geng, Dechun

doi:10.1016/j.actbio.2017.01.034

Cited by 68 publications

(57 citation statements)

References 50 publications

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“…When taking only the diaphysis for analysis, it was found that β‐catenin activation was more powerful than PTH in accelerating diaphyseal fracture healing, which consistent with the findings of Agholme and Sandberg et al . And they promoted diaphysis fracture healing better than wild group, and promoted the expression levels of OCN, RUNX2, LEF‐1 in the defect, as others report . In rat, a low dose of PTH enhanced metaphyseal repair, whereas the Scl‐ab had mainly cortical bone effects with less influence on metaphyseal healing.…”

Section: Discussionsupporting

confidence: 87%

Different effects of Wnt/β‐catenin activation and parathyroid hormone on diaphyseal and metaphyseal in the early phase of femur bone healing of mice

Liu

Chen

et al. 2019

Clin Exp Pharma Physio

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Summary Parathyroid hormone (PTH) and agents related to the manipulation of Wnt/β‐catenin signalling are two promising anabolic anti‐osteoporotic therapies that have been shown to promote the healing of bone fractures. Now, it is widely accepted that cortical bone and trabecular bone are two different compartments, and should be treated as separate compartments in pathological processes, such as fracture healing. It is currently unknown whether PTH and the activation of β‐catenin signalling would demonstrate different effects on cortical bone and trabecular bone healing. In the current study, single 0.6‐mm cortex holes were made in the femur metaphysis and diaphysis of mice, and then, PTH application and β‐catenin activation were used to observe the promoting effect on bone healing. The effects of β‐catenin and PTH signalling on fracture healing were observed by X‐ray and CT at 3, 6, and 14 days after fracture, and the levels of β‐catenin were detected by RT‐PCR assay, and the number of specific antigen‐positive cells of BRDU, OCN, RUNX2 was counted by immunohistochemical staining. While β‐catenin activation and PTH were found to demonstrate similar effects on accelerating metaphyseal bone healing, activation of β‐catenin showed a more striking effect than PTH on promoting diaphyseal bone healing. These findings might be helpful for selecting proper medication to accelerate fracture healing of different bone compartments.

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Section: Discussionsupporting

confidence: 87%

Different effects of Wnt/β‐catenin activation and parathyroid hormone on diaphyseal and metaphyseal in the early phase of femur bone healing of mice

Liu

Chen

et al. 2019

Clin Exp Pharma Physio

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“…Except for anabolic effects on bone, melatonin is able to suppress bone loss by regulating immune disorder and reversing the abnormal cytokine framework back to normal status. Many studies have suggested that an excessive dose (1–100 μM) of melatonin could alleviate foreigner antigen‐induced negative nonspecific responses and inflammatory cytokines, including TNF‐α and IL‐1β, which helped to inhibit the acceleration of bone loss (Lian et al, ; Liu et al, ; Ping et al, ). However, Zhang et al found that a lower concentration of melatonin played a more beneficial role (50 mg·kg −1 was better than 100 mg·kg −1 ) in improving bone microstructure in type 2 diabetic osteoporosis rats by regulating bone immunity (Zhang et al, ).…”

Section: Discussionmentioning

confidence: 99%

Melatonin up‐regulates bone marrow mesenchymal stem cells osteogenic action but suppresses their mediated osteoclastogenesis via MT₂‐inactivated NF‐κB pathway

Zhou

Wang

et al. 2020

British J Pharmacology

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Background and Purpose: Melatonin is a neurohormone involved in bone homeostasis. Melatonin directs bone remodelling and the role of bone marrow mesenchymal stem cells (BMMSCs) in the regulating melatonin-mediated bone formationresorption balance remains undefined. Experimental Approach: Osteoporosis models were established and bone tissue and serum were collected to test the effects of melatonin on bone homeostasis. Melatonin receptors were knocked down, the NF-κB signalling pathway and receptor activator of NF-κB ligand (RANKL) expression were investigated. Communication between bone marrow mesenchymal stem cells and osteoclasts was detected with directcontact or indirect-contact system. Key Results: Bone loss and microstructure disorder in mice were reversed after melatonin treatment, as a result of anabolic and anti-resorptive effects. In vitro, a physiological (low) concentration of melatonin promoted the bone marrow mesenchymal stem cells, osteogenic lineage commitment and extracellular mineralization but had no impact on extracellular matrix synthesis. After MT knockdown, especially MT 2 , the positive effects of melatonin on osteogenesis were attenuated. The canonical NF-κB signalling pathway was the first discovered downstream signalling pathway after MT receptor activation and was found to be down-regulated by melatonin during osteogenesis. Melatonin suppressed BMMSC-mediated osteoclastogenesis by inhibiting RANKL production in BMMSCs and this effect only occurred when BMMSCs and osteoclast precursors were co-cultured in an indirect-contact manner. Conclusion and Implications: Our work suggests that melatonin plays a crucial role in bone balance, significantly accelerates the osteogenic differentiation of bone marrow mesenchymal stem cells by suppressing the MT 2 -dependent NF-κB signalling pathway, and down-regulates osteoclastogenesis via RANKL paracrine secretion. Abbreviations: ALP, alkaline phosphatase; BMD, bone mineral density; BMMs, bone marrow monocytes; BMMSCs, bone marrow mesenchymal stem cells; BV/TV, trabecular bone volume per total volume; Col-I, collagen I; CTX-I, C-terminal telopeptide α1 chain of type I collagen; H&E, haematoxylin and eosin; Mel, melatonin; OCN, osteocalcin; OPG, osteoprotegerin; OVX, ovariectomy; PINP, N-terminal propeptide of type I procollagen; RANK, receptor activator of NF-κB; RANKL, receptor activator of NF-κB ligand; TRAP, tartrate-resistant acid phosphatase; Tb. N, trabecular bone number; Tb. Sp, trabecular bone separation; Tb. Th, trabecular bone thickness; μCT, micro-CT.

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“…Melatonin has gained growing attention as an attractive therapeutic candidate for bone-loss diseases based on its following roles in bone homeostasis: 1) melatonin induces differentiation and mineralization of osteogenic precursor cells in vitro via multiple acknowledged signaling pathways, including MAPKs, BMP-Smad, and Wnt-b-catenin (23)(24)(25)(26); 2) melatonin suppresses osteoclastogenesis through down-regulation of the NF-kB pathway and modulation of the balance between receptor activator NF-kB ligand and osteoprotegerin expression (27,28); 3) melatonin administration significantly increases bone mineral density (BMD) in animal models of osteoporosis through its dual effect of enhancing bone formation by osteogenic precursor cells and suppressing bone resorption by OCs (29,30); 4) melatonin administration has shown encouraging outcomes of increased femoral neck and vertebral BMD and changes in the bone resorptionbone formation ratio in clinical trials for the treatment of postmenopausal osteoporosis (31-33); 5) melatonin is an over-the-counter inexpensive supplement commonly used to improve sleep quality and psychologic well-being for elderly and menopausal populations, which has great overlap with the osteoporosis community (34). These results strongly indicate that melatonin has great potential for the treatment of osteoporosis.…”

Section: Chronic Inflammation-induced Bone Loss Is An Important Causementioning

confidence: 99%

Wnt4 signaling mediates protective effects of melatonin on new bone formation in an inflammatory environment

Wang

et al. 2019

FASEB j.

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Growing evidence shows that the inhibitory effect of inflammatory cytokines on new bone formation by osteogenic precursor cells is a critical cause of net bone‐density reduction. Melatonin has been proven to be a potential therapeutic candidate for osteoporosis. However, whether it is capable of antagonizing the suppressing effect of inflammatory cytokines on osteogenic precursor cells is so far elusive. In this study, using the cell culture system of human bone marrow stromal cells and MC3T3‐E1 preosteoblasts, we recorded the following vital observations that provided insights of melatonin‐induced bone formation: 1) melatonin induced bone formation in both normal and inflammatory conditions; 2) Wnt4 was essential for melatonin‐induced bone formation in inflammatory stimulation; 3) melatonin‐ and Wnt4‐induced bone formation occurred via activation of β‐catenin and p38‐JNK MAPK pathways by interaction with a distinct frizzled LDL receptor‐related protein complex; 4) melatonin suppressed the inhibitory effect of NF‐κB on osteogenesis in a Wnt4‐dependent manner; and 5) melatonin induced Wnt4 expression through the ERK1/2‐Pax2‐Egr1 pathway. In summary, we showed a novel mechanism of melatonin‐induced bone formation in an inflammatory environment. Melatonin‐induced Wnt4 expression is essential for its osteoinductive effect and the inhibitory effect of NF‐κB on bone formation. Our novel findings may provide useful information for its potential translational application.—Li, X., Li, Z., Wang, J., Li, Z., Cui, H., Dai, G., Chen, S., Zhang, M., Zheng, Z., Zhan, Z., Liu, H. Wnt4 signaling mediates protective effects of melatonin on new bone formation in an inflammatory environment. FASEB J. 33, 10126–10139 (2019). http://www.fasebj.org

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Melatonin attenuates titanium particle-induced osteolysis via activation of Wnt/β-catenin signaling pathway

Cited by 68 publications

References 50 publications

Different effects of Wnt/β‐catenin activation and parathyroid hormone on diaphyseal and metaphyseal in the early phase of femur bone healing of mice

Different effects of Wnt/β‐catenin activation and parathyroid hormone on diaphyseal and metaphyseal in the early phase of femur bone healing of mice

Melatonin up‐regulates bone marrow mesenchymal stem cells osteogenic action but suppresses their mediated osteoclastogenesis via MT₂‐inactivated NF‐κB pathway

Wnt4 signaling mediates protective effects of melatonin on new bone formation in an inflammatory environment

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Melatonin attenuates titanium particle-induced osteolysis via activation of Wnt/β-catenin signaling pathway

Cited by 68 publications

References 50 publications

Different effects of Wnt/β‐catenin activation and parathyroid hormone on diaphyseal and metaphyseal in the early phase of femur bone healing of mice

Different effects of Wnt/β‐catenin activation and parathyroid hormone on diaphyseal and metaphyseal in the early phase of femur bone healing of mice

Melatonin up‐regulates bone marrow mesenchymal stem cells osteogenic action but suppresses their mediated osteoclastogenesis via MT2‐inactivated NF‐κB pathway

Wnt4 signaling mediates protective effects of melatonin on new bone formation in an inflammatory environment

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Melatonin up‐regulates bone marrow mesenchymal stem cells osteogenic action but suppresses their mediated osteoclastogenesis via MT₂‐inactivated NF‐κB pathway