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


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


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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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).

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