Phosphate, but Not PTH, Induces Fibroblast Growth Factor 23 (FGF-23) Expression in Skeletal Muscle

Background: Elevations in serum phosphate levels (hyperphosphatemia) are a common feature in chronic kidney disease (CKD). Phosphate metabolism is regulated by parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23), and both hormones are interconnected via feedback mechanisms. It is thought that FGF23 is mainly secreted from the bone in response to PTH and phosphate. We have previously found in mouse models of hyperphosphatemia and CKD that also skeletal muscle tissue produces FGF23 which contributes to elevations in circulating FGF23. Here, we tested whether skeletal muscle-derived FGF23 is also regulated by PTH and phosphate. Methods: In our three mouse models of hyperphosphatemia (two CKD models, i.e. mice with deletion of collagen 4a3 and mice fed an adenine-rich diet for 14 weeks; and one non-CKD model: mice fed a high-phosphate diet for 6 months) we determined serum levels of PTH. Furthermore, C2C12 and primary mouse myotubes were treated with increasing concentrations of phosphate or PTH for 24 hours, followed by the analysis of FGF23 expression by qPCR and immunocytochemistry as well as ELISA from cell supernatants. Results: As expected, in all three mouse models hyperphosphatemia was accompanied by increases in serum PTH levels. Furthermore, phosphate treatments increased the expression and the secretion of FGF23 in cultured myotubes in a dose-dependent manner. In contrast, PTH had no effect on FGF23 in myotubes. Conclusion: Although serum levels of PTH and phosphate are both elevated in mouse models of hyperphosphatemia and CKD, our in vitro data suggest that of the two factors only phosphate can induce FGF23 expression in skeletal muscle. Myotubes express PTH receptors, and it needs to be determined why these cells do not respond to PTH by producing FGF23. Our finding suggests difference in the endocrine regulation of FGF23 in the skeletal muscle versus bone. Our ongoing studies aim to determine the role of skeletal muscle-derived FGF23. Funding: NIDDK Support