A novel role for dopamine signaling in the pathogenesis of bone loss from the atypical antipsychotic drug risperidone in female mice.
A novel role for dopamine signaling in the pathogenesis of bone loss from the atypical antipsychotic drug risperidone in female mice.
复制标题
多巴胺信号传导在雌性小鼠中非典型抗精神病药物利投资利培酮中骨丢失的发病机理中的一种新作用。
DOI：
10.1016/j.bone.2017.07.008
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发表时间：
2017-10
期刊：
影响因子：
4.1
通讯作者：
Houseknecht KL
中科院分区：
文献类型：
--
作者：
Motyl KJ;Beauchemin M;Barlow D;Le PT;Nagano K;Treyball A;Contractor A;Baron R;Rosen CJ;Houseknecht KL
非典型抗精神病(AA)药物，包括利培酮(RIS)，用于治疗精神分裂症、双相情感障碍和自闭症，并在标签外开出用于其他精神健康问题。AA类药物与肥胖和2型糖尿病的严重代谢副作用有关。横断面和纵向数据还显示，利培酮会导致男性和女性的骨质流失并增加骨折风险。RIS的骨丢失有几种潜在的机制。一种是多巴胺受体拮抗引起的高催乳素血症所致的性腺功能低下。然而，许多患者的催乳素水平正常；此外，我们还证明，心得安可以通过抑制β肾上腺素能受体的激活来阻止小鼠RIS的骨丢失，这表明交感神经系统在其中发挥了病理作用。此外，当我们每天用RIS或赋形剂治疗卵巢切除(OVX)和假手术小鼠8周时，我们证明RIS导致假手术和OVX小鼠都有显著的骨小梁丢失。RIS直接抑制了Sham和OVX小鼠的成骨细胞数量，但增加了OVX小鼠的破骨细胞数量和表面，这可能是导致骨丢失加剧的原因。因此，仅有性腺功能减退不能解释RIS引起的骨丢失。在目前的研究中，我们证明了多巴胺和RIS存在于骨髓间室，并且RIS可以通过多巴胺受体直接作用于骨细胞。我们对AA药物对骨骼的直接和间接影响的发现，对于目前和未来研究AA药物改变骨骼的机制的临床和翻译研究是相关的。
Atypical antipsychotic (AA) drugs, including risperidone (RIS), are used to treat schizophrenia, bipolar disorder, and autism, and are prescribed off-label for other mental health issues. AA drugs are associated with severe metabolic side effects of obesity and type 2 diabetes. Cross-sectional and longitudinal data also show that risperidone causes bone loss and increases fracture risk in both men and women. There are several potential mechanisms of bone loss from RIS. One is hypogonadism due to hyperprolactinemia from dopamine receptor antagonism. However, many patients have normal prolactin levels; moreover we demonstrated that bone loss from RIS in mice can be blocked by inhibition of β-adrenergic receptor activation with propranolol, suggesting the sympathetic nervous system (SNS) plays a pathological role. Further, when, we treated ovariectomized (OVX) and sham operated mice daily for 8 weeks with RIS or vehicle we demonstrated that RIS causes significant trabecular bone loss in both sham operated and OVX mice. RIS directly suppressed osteoblast number in both sham and OVX mice, but increased osteoclast number and surface in OVX mice alone, potentially accounting for the augmented bone loss. Thus, hypogonadism alone cannot explain RIS induced bone loss. In the current study, we show that dopamine and RIS are present in the bone marrow compartment and that RIS can exert its effects directly on bone cells via dopamine receptors. Our findings of both direct and indirect effects of AA drugs on bone are relevant for current and future clinical and translational studies investigating the mechanism of skeletal changes from AA drugs.
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影响因子：
4.9
作者：
Ledesma-Colunga MG;Adán N;Ortiz G;Solís-Gutiérrez M;López-Barrera F;Martínez de la Escalera G;Clapp C
通讯作者：
Clapp C
影响因子：
4.1
作者：
Bliziotes, M;McLoughlin, S;Caron, MG
通讯作者：
Caron, MG
影响因子：
5.3
作者：
Kishimoto, Taishiro;Watanabe, Koichiro;Kashima, Haruo
通讯作者：
Kashima, Haruo
影响因子：
5.3
作者：
Becker, D;Liver, O;Weiss, M
通讯作者：
Weiss, M
影响因子：
4.5
作者：
Meaney, A. M.;O'Keane, V.
通讯作者：
O'Keane, V.