基于Circ-Insig2 /miR-421-3p/FOXO3轴调控成骨细胞自噬探讨抗精神病药利培酮导致骨质疏松的作用及机制

精神分裂症是一种常见精神病，长期使用抗精神病药可导致患者骨质疏松，致残危害很大，但分子机制不明。本课题组首次发现，抗精神病药利培酮显著下调精神分裂症小鼠骨组织中Circ-Insig2。预实验表明，利培酮处理的成骨细胞过表达Circ-Insig2后，自噬水平提高，促进成骨分化，且Circ-Insig2含有miR-421-3p应答元件并调控其靶基因FOXO3表达。我们推测，利培酮可通过下调成骨细胞中Circ-Insig2表达调控miR-421-3p及其靶基因FOXO3表达介导成骨细胞自噬水平下降，引起OP效应。本项目拟通过构建精神分裂症动物模型，体内外实验相结合，明确Circ-Insig2在利培酮介导自噬引发OP中的功能，揭示Circ-Insig2吸附miR-421-3p调控FOXO3的分子机制。本项目旨在揭示利培酮引发OP效应的新机制，以期为降低利培酮临床用药的潜在危险因素提供科学依据。

Schizophrenia is a common psychiatric disorder, and long-term use of antipsychotics can lead to Osteoporosis (OP). However, their molecular mechanisms are unclear. We found that risperidone, an antipsychotic, significantly down-regulated circ-insig2 in the bone tissue of the schizophrenia animal model group. Preliminary experiments showed that after risperidone-treated osteoblasts overexpressed circ-insig2, autophagy level was improved and osteogenic differentiation was promoted. The bioinformatics predictions show that circ-insig2 contained mir-421-3p response elements and mir-421-3p have binding sites of FOXO3. Previous study showed circ-insig2 could regulate the expression of mir-421-3p and FOXO3. It is well known that FOXO3 can promote osteogenic differentiation by inducing autophagy. We hypothesized that risperidone could regulate mir-421-3p and its target gene FOXO3 expression by down-regulating circ-insig2 expression in osteoblasts and mediate the decline of autophagy level in osteoblasts, leading to OP effect, which may be a new mechanism of risperidone causing OP. To confirm this hypothesis, this project intends to establish an animal model of schizophrenia and combine in vivo and in vitro experiments to clarify the role of circ-insig2 in risperidone-mediated autophagy initiation OP, and to reveal the molecular mechanism of circ-insig2 adsorption mir-421-3p in regulating FOXO3.This project aims to reveal the new mechanism of OP effect induced by risperidone, so as to provide scientific basis for the full evaluation of potential risk factors of risperidone in clinical use.