Division of Life Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kanazawa, Ishikawa, 920-1192, Japan.
Noto Marine Laboratory, Institute of Nature and Environmental Technology, Division of Marine Environmental Studies, Kanazawa University, Noto-cho, Ishikawa, 927-0553, Japan.
Biochem Biophys Res Commun. 2020 Oct 1;530(4):644-650. doi: 10.1016/j.bbrc.2020.07.075. Epub 2020 Aug 5.
Melatonin has been implicated in the regulation of bone metabolism; however, the molecular mechanisms underlying its involvement in fracture healing are still obscure. We previously developed an in vivo fracture healing model using the scale of a double-transgenic zebrafish, trap:GFP; osterix:mCherry, which labels osteoclasts and osteoblasts with GFP and mCherry, respectively. Here we show using this model that melatonin inhibits both osteoblast and osteoclast differentiation under fracture stress through the repression of Erk signaling in epidermal cells of the scale. Melatonin treatment resulted in reduced numbers of both osteoblasts and osteoclasts in the fractured scale. Immunochemistry analysis revealed that Erk signals in epidermal cells, which express melatonin receptors, were greatly enhanced in response to fracture stress, but this enhancement was blocked by melatonin treatment. Moreover, inhibition of Erk signaling phenocopied the effects of melatonin treatment in the fractured scale. Collectively, these data suggest that the activation of epidermal Erk signaling is required for both osteoblast and osteoclast differentiation in the early stage of fracture healing, and melatonin suppresses epidermal Erk signaling, leading to impaired fracture healing.
褪黑素参与了骨代谢的调节；然而，其在骨折愈合中的作用的分子机制仍不清楚。我们之前开发了一种使用双转基因斑马鱼鳞片的体内骨折愈合模型，trap:GFP;osterix:mCherry，分别用 GFP 和 mCherry 标记破骨细胞和成骨细胞。在这里，我们使用该模型表明，褪黑素通过抑制表皮细胞中的 Erk 信号通路来抑制骨折应激下的成骨细胞和成骨细胞分化。褪黑素处理导致骨折鳞片中成骨细胞和破骨细胞数量减少。免疫化学分析显示，表达褪黑素受体的表皮细胞中的 Erk 信号对骨折应激有很大的增强作用，但这种增强被褪黑素处理所阻断。此外，Erk 信号通路的抑制作用模拟了褪黑素处理在骨折鳞片中的作用。总的来说，这些数据表明，表皮 Erk 信号的激活是骨折愈合早期成骨细胞和成骨细胞分化所必需的，而褪黑素抑制表皮 Erk 信号通路，导致骨折愈合受损。
