Department of Pharmacology, School of Dentistry, Showa University, Tokyo, 142-8555, Japan; Pharmacological Research Center, Showa University, Tokyo, 142-8555, Japan.
Department of Pharmacology, School of Dentistry, Showa University, Tokyo, 142-8555, Japan; Pharmacological Research Center, Showa University, Tokyo, 142-8555, Japan.
Biomed Pharmacother. 2019 Oct;118:109101. doi: 10.1016/j.biopha.2019.109101. Epub 2019 Jul 14.
Glucocorticoids (GCs) play an important role in the stress reaction and function in the development of multiple tissues in our body. When given chronically in supraphysiologic doses, GCs are associated with orthodontic tooth movement, with serious side effects and particularly adverse effects on bone metabolism. However, the effects of steroids on bone cell dynamics are incompletely understood. Therefore, in this present study we examined the participation of osteoblasts and osteoclasts in osterix-DsRed/TRAP-EGFP double transgenic (Tg) medaka treated with synthetic GCs. Chronic continuous administration of prednisolone (PN) significantly reduced the fluorescence signals in the whole body of both osterix-DsRed and TRAP-EGFP medaka at 18 days, and those of the pharyngeal bone and tooth region at 32 days. To examine the capacity of the medaka for fracture healing during chronic administration of PN, we caused a fracture of a part of the bony fin ray at 18 days after the initiation of PN continuous administration. The bone fracture healing was significantly delayed by 32 days, accompanied by decreased signal area of both osterix-DsRed and TRAP-EGFP compared with that of the control. Next, to investigate the effect of acute administration of GC on the fracture healing, we started administration of dexamethasone (DX) immediately after the bone fracture, and this administration lasted during the 11 days of fracture healing. The results showed that the TRAP-EGFP-positive osteoclasts were reduced in area, but not the osterix-DsRed-positive osteoblasts. Lastly, to confirm the function of the glucocorticoid receptor in bone healing, we generated glucocorticoid receptor 2-deficient medaka (gr2). The fluorescent signal area of osterix-DsRed and TRAP-EGFP were increased at bone fracture sites in these fish, and DX treatment of them decreased the TRAP-EGFP signal area compared with that for the control fish. Our results indicate that GRs negatively regulated osteoclast recruitment and the accumulation of osteoblasts in bone fracture healing.
糖皮质激素（GCs）在应激反应中发挥重要作用，并在体内多种组织的发育中发挥作用。当以超生理剂量长期给予时，GCs 与正畸牙齿移动有关，具有严重的副作用，特别是对骨代谢有不良影响。然而，类固醇对骨细胞动力学的影响尚不完全清楚。因此，在本研究中，我们研究了合成 GCs 处理的成骨细胞和破骨细胞在骨形成蛋白 2 （osterix）-DsRed/TRAP-EGFP 双转基因（Tg）斑马鱼中的参与。慢性连续给予泼尼松龙（PN）可显著降低 18 天时 osterix-DsRed 和 TRAP-EGFP 斑马鱼整个身体以及 32 天时咽骨和牙齿区域的荧光信号。为了研究慢性 PN 给药期间斑马鱼骨折愈合的能力，我们在 PN 连续给药 18 天后引起部分骨鳍射线骨折。与对照组相比，骨折愈合明显延迟 32 天，同时 osterix-DsRed 和 TRAP-EGFP 的信号面积减少。接下来，为了研究 GC 对骨折愈合的急性作用，我们在骨骨折后立即开始给予地塞米松（DX）给药，并在骨折愈合的 11 天内持续给药。结果表明，TRAP-EGFP 阳性破骨细胞的面积减少，但 osterix-DsRed 阳性成骨细胞的面积没有减少。最后，为了确认糖皮质激素受体在骨愈合中的作用，我们生成了糖皮质激素受体 2 缺陷型斑马鱼（gr2）。在这些鱼的骨折部位，osterix-DsRed 和 TRAP-EGFP 的荧光信号面积增加，并且它们的 DX 处理与对照鱼相比降低了 TRAP-EGFP 信号面积。我们的结果表明，GR 负调节破骨细胞募集和骨骨折愈合中骨细胞的积累。
