Celastrol Attenuates FGF23 Expression in Osteoblasts by Inhibiting STAT3 Activation

Introduction In this study, we aim to investigate the mechanism by which extracellular phosphate (Pi) regulates the transcription of fibroblast growth factor 23 (FGF23) in osteoblasts and the effects of celastrol on FGF23 expression in UMR-106 cells and in chronic kidney disease (CKD) rat models. Methods We used Pi to induce FGF23 expression in a rat osteoblastic cell line as a model and then treated the cells with celastrol. The cytotoxicity of Pi and celastrol was assessed using the CCK-8 assay. FGF23 expression was measured using real-time quantitative PCR (RT-qPCR), and its promoter activity was evaluated using luciferase reporter assays. To detect active signal transducer and activator of transcription 3 (STAT3), immunofluorescence and Western blotting were performed. The 5/6 nephrectomized rat model was established to investigate the effects of celastrol on FGF23 expression in vivo. An enzyme-linked immunosorbent assay was carried out to examine serum FGF23 levels in rats. RT-qPCR detected the mRNA levels of FGF23 and STAT3 in the femurs of CKD rats. Results We found that high Pi activated STAT3 and promoted its nuclear translocation, leading to elevated FGF23 expression, which was suppressed by celastrol. Additionally, in rats subjected to 5/6 nephrectomy with high serum Pi levels, serum FGF23 levels and skeletal STAT3 expression were significantly decreased after celastrol treatment. Discussion Therefore, celastrol could have therapeutic effects on CKD by decreasing serum FGF23. Conclusion High Pi activates STAT3 and induces FGF23 expression. Furthermore, celastrol can attenuate increased FGF23 expression induced by high Pi, potentially via inhibition of STAT3 activation.