Selective Serotonin Reuptake Inhibitors Inhibit Human Osteoclast and Osteoblast Formation and Function
Selective Serotonin Reuptake Inhibitors Inhibit Human Osteoclast and Osteoblast Formation and Function
复制标题
选择性血清素再摄取抑制剂抑制人类破骨细胞和成骨细胞的形成和功能
DOI：
10.1016/j.biopsych.2012.11.003
复制
发表时间：
2013-07-01
影响因子：
10.6
通讯作者：
Williams, Lana J.
中科院分区：
文献类型：
--
作者：
Hodge, Jason M.;Wang, Yiming;Williams, Lana J.
背景：选择性血清素再摄取抑制剂（SSRIs）是广泛应用的抗抑郁药物，也是最常用的药物之一。越来越多的人担心，SSRIs在骨髓中的浓度高于大脑或血液，会增加骨骼的脆弱性和骨折的风险。然而，它们对人破骨细胞（OC）和成骨细胞（OB）分化的作用机制尚不清楚。方法：采用聚合酶链反应法检测血清素受体（5-HTR）、转运体（5-HTR）和色氨酸羟化酶1 （TPH1）在OC（前体和成熟）和OB（非矿化和矿化）中的表达。在5种SSRIs存在的情况下，测量OC的形成和吸收。用SSRIs培养28天的OBs评估碱性磷酸酶（ALP）和骨矿化。膜联蛋白V流式细胞术检测细胞活力和凋亡。结果：OCs和OB表达TPH1、5-HTT和5-HTR1B。5-HTR2A仅在OB中表达，而5-HTR2B的表达从前体到成熟OC均有所增加。除西酞普兰外，所有SSRIs均在1 ~ 10 μ mol/L之间呈剂量依赖性地抑制OC的形成和吸收；效价顺序：舍曲林>氟西汀>帕罗西汀>氟伏沙明>西酞普兰。同样，SSRIs（西酞普兰除外）抑制OB的ALP和骨矿化，但仅在30 μ mol/L时。SSRIs诱导OC和OB细胞凋亡的模式与抑制作用相同。血清素治疗对OC和OB参数均无影响。结论：这些数据表明SSRIs通过细胞凋亡抑制骨细胞功能的差异。这可以解释长期使用的骨质流失机制，并有助于临床选择。
Background: Selective serotonin reuptake inhibitors (SSRIs) are widely used antidepressants and one of the most commonly used medications. There is growing concern that SSRIs, which sequester in bone marrow at higher concentrations than brain or blood, increase bone fragility and fracture risk. However, their mechanism of action on human osteoclasts (OC) and osteoblasts (OB) differentiation remains unclear.Methods: Expression of serotonin receptors (5-HTR), transporter (5-HTT), and tryptophan hydroxylase 1 (TPH1) was assessed in human OC (precursors and mature) and OB (nonmineralizing and mineralizing) by polymerase chain reaction. OC formation and resorption was measured in the presence of 5 SSRIs. OBs cultured with SSRIs for 28 days were assessed for alkaline phosphatase (ALP) and bone mineralization. Cell viability and apoptosis were determined by annexin V flow cytometry.Results: OCs and OB expressed TPH1, 5-HTT, and 5-HTR1B. The 5-HTR2A was expressed only in OB, whereas 5-HTR2B expression increased from precursor to mature OC. All SSRIs (except citalopram) dose-dependently inhibited OC formation and resorption between 1 mu mol/L and 10 mu mol/L; order of potency: sertraline > fluoxetine > paroxetine > fluvoxamine > citalopram. Similarly, SSRIs (except citalopram) inhibited ALP and bone mineralization by OB but only at 30 mu mol/L. Apoptosis was induced by SSRIs in OC and OB in an identical pattern to inhibitory effects. Serotonin treatment had no effect on either OC or OB parameters.Conclusions: These data demonstrate that SSRIs differentially inhibit bone cell function via apoptosis. This may explain the mechanisms of bone loss with chronic use and aid clinical choices.