Abstract
BackgroundThe 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 (γ)-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.MethodsCBSCs were extracted from C57BL/6 mice and were identified by flow cytometry. Then CBSCs were subjected to 6 Gy γ-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.ResultsThe 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-α) 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-α levels than in the irradiation and the Matrigel groups (P < 0.05).ConclusionThis study suggested that melatonin could protect CBSCs against γ-ray radiation and assist in the healing of postradiation bone defects.
Highlights
The healing of bone defects can be challenging for clinicians to manage, especially after exposure to ionizing radiation
This study suggested that melatonin could protect Cortical bone-derived stem cells (CBSCs) against γ-ray radiation and assist in the heal‐ ing of postradiation bone defects
Melatonin attenuates radiation‐induced CBSCs injury Melatonin alleviates radiation‐induced the loss of self‐renewal and osteogenic capacity of CBSCs We extracted and cultured CBSCs from femurs according to previously described protocols (Fig. 1a)
Summary
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 (γ)-ray radiation have been shown to inhibit bone formation and increase the risk of fractures. Gamma (γ)-rays are highly penetrating electromagnetic ionizing radiation that have been extensively applied in diagnostic radiography, radiation oncology, and military weapons [1]. Ionizing radiation has been reported to be closely associated with bone metabolism. Therapeutic or accidental ionizing radiation exposure could induce bone remodeling disorders, including malignancy, avascular necrosis, arrest of bone growth, fracture, and osteopenia [5, 6]. The mechanisms of radiation-induced bone loss at the cellular level are yet to be fully elucidated
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