The Selective Serotonin Reuptake Inhibitor Fluoxetine Directly Inhibits Osteoblast Differentiation and Mineralization During Fracture Healing in Mice.
The Selective Serotonin Reuptake Inhibitor Fluoxetine Directly Inhibits Osteoblast Differentiation and Mineralization During Fracture Healing in Mice.
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DOI：
10.1002/jbmr.3045
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发表时间：
2017-04
期刊：
影响因子：
--
通讯作者：
Leucht P
中科院分区：
文献类型：
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作者：
Bradaschia-Correa V;Josephson AM;Mehta D;Mizrahi M;Neibart SS;Liu C;Kennedy OD;Castillo AB;Egol KA;Leucht P
长期使用选择性5-羟色胺再摄取抑制剂(SSRI)治疗抑郁症与骨质疏松有关。在这项研究中，我们研究了长期使用SSRI对两种骨再生模型小鼠骨折愈合的影响。首先，我们对股骨骨折模型中的软骨内骨愈合进行了全面的分析。用最常用的SSRI药物氟西汀治疗的C57/BL6小鼠在骨折后14天形成了正常的软骨痂，28天时显示出明显较小且生物力学较弱的骨性硬骨痂。为了进一步剖析导致较小骨痂再生的机制，我们使用了膜内骨愈合模型，发现氟西汀治疗在伤后7天和14天导致骨痂明显减少。为了验证氟西汀治疗后的小骨再生是否由成骨分化和/或矿化抑制所致，我们采用了体外实验，证实氟西汀治疗减少了成骨分化和矿化，并且这种作用是不依赖于5-羟色胺的。最后，在一种翻译方法中，我们测试了停止用药是否会导致再生潜力的恢复。然而，组织学和微CT分析显示，在这些动物中形成骨不连，骨痂内有纤维组织插入。总之，氟西汀对成骨细胞分化和矿化有直接的抑制作用，在两种不同的小鼠骨修复模型中显示出来。停用该药并没有恢复治疗潜力，而是导致修复过程完全停止。除了公认的SSRIs对骨内环境稳定的影响外，我们的研究还提供了强有力的证据表明，氟西汀的使用对骨折愈合有负面影响。
Chronic use of selective serotonin reuptake inhibitors (SSRIs) for the treatment of depression has been linked to osteoporosis. In this study, we investigated the effect of chronic SSRI use on fracture healing in two murine models of bone regeneration. First, we performed a comprehensive analysis of endochondral bone healing in a femur fracture model. C57/BL6 mice treated with fluoxetine, the most commonly prescribed SSRI, developed a normal cartilaginous soft-callus at 14 days after fracture and demonstrated a significantly smaller and biomechanically weaker bony hard-callus at 28 days. In order to further dissect the mechanism that resulted in a smaller bony regenerate, we used an intramembranous model of bone healing and revealed that fluoxetine treatment resulted in a significantly smaller bony callus at 7 and 14 days postinjury. In order to test whether the smaller bony regenerate following fluoxetine treatment was caused by an inhibition of osteogenic differentiation and/or mineralization, we employed in vitro experiments, which established that fluoxetine treatment decreases osteogenic differentiation and mineralization and that this effect is serotonin-independent. Finally, in a translational approach, we tested whether cessation of the medication would result in restoration of the regenerative potential. However, histologic and µCT analysis revealed non-union formation in these animals with fibrous tissue interposition within the callus. In conclusion, fluoxetine exerts a direct, inhibitory effect on osteoblast differentiation and mineralization, shown in two disparate murine models of bone repair. Discontinuation of the drug did not result in restoration of the healing potential, but rather led to complete arrest of the repair process. Besides the well-established effect of SSRIs on bone homeostasis, our study provides strong evidence that fluoxetine use negatively impacts fracture healing.