Organic phosphate but not inorganic phosphate regulates Fgf23 expression through MAPK and TGF-ꞵ signaling
Danielle M.A. Ratsma,
Max Muller,
Marijke Koedam,
Johannes P.T.M. van Leeuwen,
M. Carola Zillikens,
Bram C.J. van der Eerden
Affiliations
Danielle M.A. Ratsma
Laboratory for Calcium and Bone Metabolism and Erasmus MC Bone Centre, Department of Internal Medicine, Erasmus MC, Erasmus University Medical Center, Rotterdam, the Netherlands
Max Muller
Laboratory for Calcium and Bone Metabolism and Erasmus MC Bone Centre, Department of Internal Medicine, Erasmus MC, Erasmus University Medical Center, Rotterdam, the Netherlands
Marijke Koedam
Laboratory for Calcium and Bone Metabolism and Erasmus MC Bone Centre, Department of Internal Medicine, Erasmus MC, Erasmus University Medical Center, Rotterdam, the Netherlands
Johannes P.T.M. van Leeuwen
Laboratory for Calcium and Bone Metabolism and Erasmus MC Bone Centre, Department of Internal Medicine, Erasmus MC, Erasmus University Medical Center, Rotterdam, the Netherlands
M. Carola Zillikens
Laboratory for Calcium and Bone Metabolism and Erasmus MC Bone Centre, Department of Internal Medicine, Erasmus MC, Erasmus University Medical Center, Rotterdam, the Netherlands
Bram C.J. van der Eerden
Laboratory for Calcium and Bone Metabolism and Erasmus MC Bone Centre, Department of Internal Medicine, Erasmus MC, Erasmus University Medical Center, Rotterdam, the Netherlands; Corresponding author
Summary: One of the main regulators of phosphate homeostasis is fibroblast growth factor 23 (FGF23), secreted by osteocytes. The effects of organic versus inorganic dietary phosphate on this homeostasis are unclear. This study used MC3T3-E1 FGF23-producing cells to examine the transcriptomic responses to these phosphates. Most importantly, the expression and secretion of FGF23 were only increased in response to organic phosphate. Gene ontology terms related to a response to environmental change were only enriched in cells treated with organic phosphate while cells treated with inorganic phosphate were enriched for terms associated with regulation of cellular phosphate metabolism. Inhibition of MAPK signaling diminished the response of Fgf23 to organic phosphate, suggesting it activates FGF23. TGF-β signaling inhibition increased Fgf23 expression after the addition of organic phosphate, while the negative TGF-β regulator Skil decreased this response. In summary, the observed differential response of FGF23-producing to phosphate types may have consequences for phosphate homeostasis.
