Risperidone accelerates bone loss in mice models of schizophrenia by inhibiting osteoblast autophagy.

Background: Risperidone (RIS) is the first-line drug in the clinical treatment of schizophrenia, and long-term use may lead to bone loss and even osteoporosis. This study investigated whether the mechanism of RIS-induced bone loss is related to autophagy. Methods: The schizophrenia mice were established with the administration of MK-801. Then, RIS were injected, or autophagy inducer rapamycin (RAPA) co-injected for 8 weeks. Cognitive performance was determined by the novel object recognition and Open field tests. Bone loss of schizophrenia mice were assessed using microCT, H&E staining, ALP staining, ARS staining and WB, respectively. Autophagy of schizophrenia mice were detected by immunofluorescence, transmission electron microscopy (TEM) and WB, respectively. In addition, osteogenic differentiation of MC3T3-E1 and BMSCs cells were assessed using H&E staining, ALP staining, ARS staining and WB, respectively. Results: In the present study, we found that RIS treatment can promote bone loss in schizophrenia mice and inhibit osteogenic differentiation of MC3T3-E1 and BMSCs cells. Interesting, the number of autophagosome and autophagy-related protein expression were decreased after RIS treatment. However, the bone loss and inhibition of osteogenic differentiation induced by RIS in schizophrenia mice were reversed by autophagy inducer RAPA. Conclusion: RIS significantly increased bone loss and inhibited osteogenic differentiation in schizophrenia mice; the underlying mechanism entails suppressing osteoblast autophagy.