利培酮,一种非典型的抗精神病药,阻碍血清素和多巴胺受体系统。同时,已知肿瘤坏死因子-α(TNF-α)参与调节成骨细胞的功能。因此,本研究旨在探讨利培酮对成骨细胞功能的影响是否与TNF-α和特殊的富含AT的序列结合蛋白(SATB2)有关。
首先,我们搜索了DGIdb,MEM和GeneCards数据库,以确定利培酮对成骨细胞的影响所涉及的关键因素,以及他们的互动。之后,用携带si-TNF-α的慢病毒转导成骨细胞MC3T3-E1,si-SATB2或两者,随后用利培酮处理。各种能力,包括分化,观察不同处理后成骨细胞的自噬和凋亡情况。最后,动物实验与利培酮单独或与慢病毒一起进行,以验证利培酮在体内的功能和机制。
发现利培酮可能促进TNF-α表达,从而抑制SATB2的表达影响成骨细胞的自噬和凋亡。此外,正如我们的实验发现所示,利培酮治疗抑制分化和自噬,促进成骨细胞的凋亡,OPG水平升高证明了这一点,p62,切割的PARP1,切割的caspase-3,切割的caspase-8和切割的caspase-9,并降低LC3II/I的水平,Beclin1,胶原蛋白I,还有RANKL.此外,还发现利培酮可以通过提高TNF-α的表达来下调SATB2,从而在体外和体内抑制成骨细胞的分化和自噬并增强其凋亡。
集体,我们的研究结果表明,利培酮通过抑制自噬和通过TNF-α介导的SATB2下调促进凋亡来影响成骨细胞的分化。
Risperidone, an atypical antipsychotic, impedes serotonin and dopamine receptor systems. Meanwhile, tumor necrosis factor-α (TNF-α) is known to participate in regulating osteoblast functions. Consequently, the current study aimed to investigate whether the influences of Risperidone on osteoblast functions are associated with TNF-α and special AT-rich sequence-binding protein (
SATB2).
Firstly, we searched the DGIdb, MEM and GeneCards databases to identify the critical factors involved in the effects of Risperidone on osteoblasts, as well as their interactions. Afterwards, osteoblast cell line MC3T3-E1 was transduced with lentivirus carrying si-TNF-α, si-
SATB2 or both and subsequently treated with Risperidone. Various abilities including differentiation, autophagy and apoptosis of osteoblasts were examined after different treatments. Finally, animal experiments were performed with Risperidone alone or together with lentivirus to verify the function of Risperidone in vivo and the mechanism.
It was found that Risperidone might promote TNF-α expression, thereby inhibiting the expression of
SATB2 to affect the autophagy and apoptosis in osteoblasts. Furthermore, as shown by our experimental findings, Risperidone treatment inhibited the differentiation and autophagy, and promoted the apoptosis of osteoblasts, as evidenced by elevated levels of OPG, p62, cleaved PARP1, cleaved caspase-3, cleaved caspase-8, and cleaved caspase-9, and reduced levels of LC3 II/I, Beclin1, collagen I, and RANKL. In addition, Risperidone was also found to elevate the expression of TNF-α to down-regulate
SATB2, thereby inhibiting the differentiation and autophagy and enhancing the apoptosis of osteoblasts in vitro and in vivo.
Collectively, our findings indicated that Risperidone affects the differentiation of osteoblasts by inhibiting autophagy and enhancing apoptosis via TNF-α-mediated down-regulation of
SATB2.