Involvement of the TNF-α/SATB2 axis in the induced apoptosis and inhibited autophagy of osteoblasts by the antipsychotic Risperidone

Background: Risperidone, an atypical antipsychotic, impedes serotonin and dopamine receptor systems. Meanwhile, tumor necrosis factor-alpha (TNF-alpha) 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-alpha and special AT-rich sequence-binding protein (SATB2). Methods: Firstly, we searched the DGldb, 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-alpha, 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. Results: It was found that Risperidone might promote TNF-alpha 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 ofTNF-alpha to down-regulate SATB2, thereby inhibiting the differentiation and autophagy and enhancing the apoptosis of osteoblasts in vitro and in vivo. Conclusions: Collectively, our findings indicated that Risperidone affects the differentiation of osteoblasts by inhibiting autophagy and enhancing apoptosis via TNF-alpha-mediated down-regulation of SATB2.

Automated summary

In this study, it was found that Risperidone affects the functions of osteoblasts by regulating TNF-alpha and SATB2. Risperidone promotes TNF-alpha expression, inhibiting SATB2 and leading to inhibited differentiation, enhanced autophagy, and apoptosis of osteoblasts.