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Melatonin interrupts osteoclast functioning and suppresses tumor-secreted RANKL expression: implications for bone metastases

Oncogene volume 40, pages 1503–1515 (2021)Cite this article

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Abstract

Cancer-related bone erosion occurs frequently in bone metastasis and is associated with severe complications such as chronic bone pain, fractures, and lower survival rates. In recognition of the fact that the darkness hormone melatonin is capable of regulating bone homeostasis, we explored its therapeutic potential in bone metastasis. We found that melatonin directly reduces osteoclast differentiation, bone resorption activity and promotes apoptosis of mature osteoclasts. We also observed that melatonin inhibits RANKL production in lung and prostate cancer cells by downregulating the p38 MAPK pathway, which in turn prevents cancer-associated osteoclast differentiation. In lung and prostate bone metastasis models, twice-weekly melatonin treatment markedly reduced tumor volumes and numbers of osteolytic lesions. Melatonin also substantially lowered the numbers of TRAP-positive osteoclasts in tibia bone marrow and RANKL expression in tumor tissue. These findings show promise for melatonin in the treatment of bone metastases.

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Fig. 1: Melatonin regulates osteoclast differentiation.
Fig. 2: Melatonin affects the functions of mature osteoclasts.
Fig. 3: Melatonin regulates tumor-associated osteoclastogenesis.
Fig. 4: Melatonin regulates RANKL production in cancer cells.
Fig. 5: Melatonin affects in vivo tumor growth and bone erosion.
Fig. 6: Schema depicting the effects of melatonin in osteolytic bone disease.

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Acknowledgements

We would like to thank Iona J. MacDonald from China Medical University for her English language revision of this paper.

Funding

This study was supported by grants from Taiwan’s Ministry of Science and Technology (MOST 108-2320-B-039-026-, MOST 109-2320-B-341-002-), China Medical University Hospital (DMR-110-102), Shin Kong Wu Ho-Su Memorial Hospital (2020SKHBND001), China Medical University under the Higher Education Sprout Project, Ministry of Education, Taiwan (CMRC-CHM-3-1), Asia University Hospital (10951002) and Chung Shan Medical University Hospital, Taiwan (CSH-2020-E-001-Y3).

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  1. These authors contributed equally: Po-I Liu, An-Chen Chang

Authors and Affiliations

  1. Graduate Institute of Biomedical Science, China Medical University, Taichung, Taiwan

    Po-I Liu, Jiun-Lin Lai, Ya-Jing Jiang, Wei-Chien Huang & Chih-Hsin Tang

  2. Department of General Thoracic Surgery, Asia University Hospital, Taichung, Taiwan

    Po-I Liu

  3. Translational Medicine Center, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan

    An-Chen Chang & Po-Chun Chen

  4. Department of Urology, Buddhist Tzu Chi General Hospital Taichung Branch, Taichung, Taiwan

    Tien-Huang Lin

  5. School of Post-Baccalaureate Chinese Medicine, Tzu Chi University, Hualien, Taiwan

    Tien-Huang Lin

  6. Department of Orthopedic Surgery, China Medical University Hospital, Taichung, Taiwan

    Chun-Hao Tsai

  7. School of Medicine, China Medical University, Taichung, Taiwan

    Chun-Hao Tsai, Liang-Wei Lin & Chih-Hsin Tang

  8. Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan

    Po-Chun Chen

  9. Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan

    Po-Chun Chen

  10. Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan

    Shun-Fa Yang

  11. Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan

    Shun-Fa Yang

  12. Chinese Medicine Research Center, China Medical University, Taichung, Taiwan

    Chih-Hsin Tang

  13. Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan

    Chih-Hsin Tang

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Contributions

Conceptualization, P-CC and C-HTang; data curation, A-CC and J-LL; formal analysis, P-IL and J-LL; investigation, P-IL and A-CC; methodology, J-LL; project administration, P-IL and A-CC; resources, T-HL and C-HTsai; software, A-CC and P-CC; supervision, W-CH, S-FY, and C-HTang; writing—original draft, P-IL and A-CC; writing—review and editing, S-FY and C-HTang.

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Correspondence to Shun-Fa Yang or Chih-Hsin Tang.

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Liu, PI., Chang, AC., Lai, JL. et al. Melatonin interrupts osteoclast functioning and suppresses tumor-secreted RANKL expression: implications for bone metastases. Oncogene 40, 1503–1515 (2021). https://doi.org/10.1038/s41388-020-01613-4

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