Abstract
Fibroblast growth factor 23 (FGF23) has been centric to the regulation of phosphate (Pi) metabolism; however, the regulatory network of FGF23 in osteocytes has not yet been defined in detail. We herein investigated the role of PTEN (phosphatase and tensin homolog deleted from chromosome 10) in this regulation. We created mice lacking PTEN expression mainly in osteocytes by crossing Pten-flox mice with Dmp1-Cre mice. The lack of PTEN in the osteocytes of these mice was associated with decreased skeletal and serum intact FGF23 levels, which, in turn, resulted in reductions of urinary Pi excretion and elevations of serum Pi levels. Mechanistically, the knockdown of PTEN expression in osteoblastic UMR106 cells activated the AKT/mTORC1 (mechanistic target of rapamycin complex 1) pathway and this was associated with reductions in Fgf23 expression. Furthermore, the suppression of Fgf23 expression by PTEN knockdown or insulin simulation in UMR106 cells was partially restored by the treatment with the mTORC1 inhibitor, rapamycin. These results suggest that FGF23 expression in osteoblastic cells is in part regulated through the AKT/mTORC1 pathway and provide new insights into our understanding of the regulatory network of Pi metabolism.
Highlights
Fibroblast growth factor 23 (FGF23) has been centric to the regulation of phosphate (Pi) metabolism; the regulatory network of FGF23 in osteocytes has not yet been defined in detail
We have provided evidence to show that the lack of PTEN in osteocytes in vivo increased serum Pi levels by decreasing intact FGF23 levels
To evaluate the efficacy of the deletion in osteocytes, we initially examined the expression of Pten in the whole femur and found that it was significantly weaker in Ptenocy−/− mice than in controls (Ptenflox/flox mice) (Fig. 1b)
Summary
Fibroblast growth factor 23 (FGF23) has been centric to the regulation of phosphate (Pi) metabolism; the regulatory network of FGF23 in osteocytes has not yet been defined in detail. FGF23 is an endocrine factor mainly produced by osteocytes that canonically acts on tissues expressing the FGF receptor and α-Klotho, such as the kidney, to regulate Pi homeostasis; the activation of the FGF23 signaling pathway decreases serum Pi levels by enhancing urinary Pi excretion. This is accomplished by reducing the localization of type IIa and IIc sodium-phosphate ( Na+/Pi) co-transporters at the brush border membrane (BBM) of the proximal tubules in the kidney. Statistical analysis was performed by Mann–Whitney U test. *p < 0.01; **p < 0.05, ns: not significantly different
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