Celastrol Attenuates Fgf23 Expression in Osteoblasts by Inhibiting STAT3 Activation

Area of Science:

• Endocrinology
• Nephrology
• Molecular Biology

Background:

• Extracellular phosphate (Pi) plays a crucial role in regulating fibroblast growth factor 23 (Fgf23) transcription in osteoblasts.
• Dysregulation of Fgf23 is implicated in various pathologies, including chronic kidney disease (CKD).

Purpose of the Study:

• To elucidate the mechanism by which extracellular phosphate regulates Fgf23 transcription.
• To investigate the effects of celastrol on Fgf23 expression in vitro and in vivo.
• To assess the therapeutic potential of celastrol in CKD models.

Main Methods:

• Utilized a rat osteoblastic cell line (UMR-106) treated with Pi and celastrol.
• Assessed cell viability using CCK-8 assay.
• Quantified Fgf23 expression via RT-qPCR and promoter activity through luciferase reporter assays.
• Detected active signal transducer and activator of transcription 3 (STAT3) using immunofluorescence and Western blotting.
• Established a 5/6 nephrectomized rat model to evaluate celastrol's in vivo effects on serum FGF23 and skeletal Stat3 expression.

Main Results:

• High Pi activated STAT3, promoting its nuclear translocation and subsequently increasing Fgf23 expression.
• Celastrol treatment suppressed Pi-induced Fgf23 expression.
• In CKD rats, celastrol administration significantly reduced elevated serum FGF23 levels and decreased skeletal Stat3 expression.

Conclusions:

• High Pi induces Fgf23 expression through STAT3 activation.
• Celastrol attenuates high Pi-induced Fgf23 expression, likely by inhibiting STAT3 activation.
• Celastrol demonstrates potential therapeutic benefits for CKD by reducing serum FGF23 levels.