PMID- 34895335 OWN - NLM STAT- MEDLINE DCOM- 20220323 LR - 20220917 IS - 2054-9369 (Electronic) IS - 2095-7467 (Print) IS - 2054-9369 (Linking) VI - 8 IP - 1 DP - 2021 Dec 12 TI - Melatonin attenuates radiation-induced cortical bone-derived stem cells injury and enhances bone repair in postradiation femoral defect model. PG - 61 LID - 10.1186/s40779-021-00355-y [doi] LID - 61 AB - BACKGROUND: The healing of bone defects can be challenging for clinicians to manage, especially after exposure to ionizing radiation. In this regard, radiation therapy and accidental exposure to gamma (gamma)-ray radiation have been shown to inhibit bone formation and increase the risk of fractures. Cortical bone-derived stem cells (CBSCs) are reportedly essential for osteogenic lineages, bone maintenance and repair. This study aimed to investigate the effects of melatonin on postradiation CBSCs and bone defect healing. METHODS: CBSCs were extracted from C57BL/6 mice and were identified by flow cytometry. Then CBSCs were subjected to 6 Gy gamma-ray radiation followed by treatment with various concentrations of melatonin. The effects of exogenous melatonin on the self-renewal and osteogenic capacity of postradiation CBSCs in vitro were analyzed. The underlying mechanisms involved in genomic stability, apoptosis and oxidative stress-related signaling were further analyzed by Western blotting, flow cytometry and immunofluorescence assays. Moreover, postradiation femoral defect models were established and treated with Matrigel and melatonin. The effects of melatonin on postradiation bone healing in vivo were evaluated by micro-CT and pathological analysis. RESULTS: The decrease in radiation-induced self-renewal and osteogenic capacity were partially reversed in postradiation CBSCs treated with melatonin (P < 0.05). Melatonin maintained genomic stability, reduced postradiation CBSC apoptosis and intracellular oxidative stress, and enhanced expression of antioxidant-related enzymes (P < 0.05). Western blotting validated the anti-inflammatory effects of melatonin by downregulating interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) levels via the extracellular regulated kinase (ERK)/nuclear factor erythroid 2-related factor 2 (NRF2)/heme oxygenase-1 (HO-1) signaling pathway. Melatonin was also found to exhibit antioxidant effects via NRF2 signaling. In vivo experiments demonstrated that the newly formed bone in the melatonin plus Matrigel group had higher trabecular bone volume per tissue volume (BV/TV) and bone mineral density values with lower IL-6 and TNF-alpha levels than in the irradiation and the Matrigel groups (P < 0.05). CONCLUSION: This study suggested that melatonin could protect CBSCs against gamma-ray radiation and assist in the healing of postradiation bone defects. CI - (c) 2021. The Author(s). FAU - Hu, Wei AU - Hu W AD - Medical School of Chinese People's Liberation Army (PLA), Beijing, 100853, China. AD - Department of Stomatology, the First Medical Centre, Chinese PLA General Hospital, Beijing, 100853, China. FAU - Liang, Jia-Wu AU - Liang JW AD - Medical School of Chinese People's Liberation Army (PLA), Beijing, 100853, China. AD - Department of Stomatology, the First Medical Centre, Chinese PLA General Hospital, Beijing, 100853, China. FAU - Liao, Song AU - Liao S AD - Medical School of Chinese People's Liberation Army (PLA), Beijing, 100853, China. FAU - Zhao, Zhi-Dong AU - Zhao ZD AD - Medical School of Chinese People's Liberation Army (PLA), Beijing, 100853, China. FAU - Wang, Yu-Xing AU - Wang YX AD - Medical School of Chinese People's Liberation Army (PLA), Beijing, 100853, China. FAU - Mao, Xiao-Fei AU - Mao XF AD - Medical School of Chinese People's Liberation Army (PLA), Beijing, 100853, China. AD - Department of Stomatology, the First Medical Centre, Chinese PLA General Hospital, Beijing, 100853, China. FAU - Hao, Si-Wei AU - Hao SW AD - Medical School of Chinese People's Liberation Army (PLA), Beijing, 100853, China. AD - Department of Stomatology, the First Medical Centre, Chinese PLA General Hospital, Beijing, 100853, China. FAU - Wang, Yi-Fan AU - Wang YF AD - Medical School of Chinese People's Liberation Army (PLA), Beijing, 100853, China. AD - Department of Stomatology, the First Medical Centre, Chinese PLA General Hospital, Beijing, 100853, China. FAU - Zhu, Heng AU - Zhu H AD - Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, 100840, China. zhudingdingabc@163.com. FAU - Guo, Bin AU - Guo B AUID- ORCID: 0000-0002-2207-9405 AD - Department of Stomatology, the First Medical Centre, Chinese PLA General Hospital, Beijing, 100853, China. guobin1110@126.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20211212 PL - England TA - Mil Med Res JT - Military Medical Research JID - 101643181 RN - JL5DK93RCL (Melatonin) SB - IM MH - Animals MH - Cortical Bone MH - Humans MH - *Melatonin/pharmacology/therapeutic use MH - Mice MH - Mice, Inbred C57BL MH - Oxidative Stress MH - Stem Cells PMC - PMC8666036 OTO - NOTNLM OT - Bone regeneration OT - Ionizing radiation OT - Melatonin OT - Stem cells COIS- The authors declare that they have no competing interests. EDAT- 2021/12/14 06:00 MHDA- 2022/03/24 06:00 PMCR- 2021/12/12 CRDT- 2021/12/13 11:46 PHST- 2021/07/12 00:00 [received] PHST- 2021/11/11 00:00 [accepted] PHST- 2021/12/13 11:46 [entrez] PHST- 2021/12/14 06:00 [pubmed] PHST- 2022/03/24 06:00 [medline] PHST- 2021/12/12 00:00 [pmc-release] AID - 10.1186/s40779-021-00355-y [pii] AID - 355 [pii] AID - 10.1186/s40779-021-00355-y [doi] PST - epublish SO - Mil Med Res. 2021 Dec 12;8(1):61. doi: 10.1186/s40779-021-00355-y.