Parathyroid hormone receptor signaling in mouse osteocytes increases the expression of fibroblast growth factor-23

RHEE Y; FARROW E; BIVI N; LEZCANO V; PLOTKIN LI; WHITE KE; BELLIDO T

BONE

ELSEVIER SCIENCE INC

Año: 2011 vol. 49 p. 636 - 643

8756-3282

Mice with constitutive activation of parathyroid hormone (PTH) receptor signaling in osteocytes (DMP1-caPTHR1 transgenic mice) exhibit increased bone mass and remodeling, two of the recognized skeletal actions of PTH. Moreover, similar to PTH administration, DMP1-caPTHR1 mice exhibit decreased expression of the osteocytederived Wnt antagonist Sost/sclerostin. We now report that PTH receptor activation also regulates in vivo and in vitro the expression of fibroblast growth factor 23 (FGF23), an osteocyte product involved in inorganic phosphate (Pi) homeostasis and bone mineralization.Whole bones and osteocytes, but not osteoblasts, from DMP1-caPTHR1 mice exhibit elevated FGF23 expression, which is corrected in double transgenic mice overexpressing Sost in osteocytes. PTH, PTH related protein (PTHrP), or a cAMP stable analog, increase FGF23 transcripts in a time- and dose-dependent manner in osteocyte-containing calvarial cell cultures. Circulating FGF23 is also elevated in DMP1- caPTHR1mice; however, plasma Pi or renal Pi reabsorption is not altered. Furthermore, the FGF23 receptor complex comprising FGFR1 and KLOTHOis expressed in osteoblastic cells; and FGFR1, GALNT3, aswell as downstream targets of FGF23 signaling, are increased in osteocytes but not in osteoblasts from DMP1-caPTHR1mice. Thus, PTH receptor signaling has the potential to modulate the endocrine and auto/paracrine functions of osteocytes by regulating FGF23 through cAMP- and Wnt-dependent mechanisms. (Pi) homeostasis and bone mineralization.Whole bones and osteocytes, but not osteoblasts, from DMP1-caPTHR1 mice exhibit elevated FGF23 expression, which is corrected in double transgenic mice overexpressing Sost in osteocytes. PTH, PTH related protein (PTHrP), or a cAMP stable analog, increase FGF23 transcripts in a time- and dose-dependent manner in osteocyte-containing calvarial cell cultures. Circulating FGF23 is also elevated in DMP1- caPTHR1mice; however, plasma Pi or renal Pi reabsorption is not altered. Furthermore, the FGF23 receptor complex comprising FGFR1 and KLOTHOis expressed in osteoblastic cells; and FGFR1, GALNT3, aswell as downstream targets of FGF23 signaling, are increased in osteocytes but not in osteoblasts from DMP1-caPTHR1mice. Thus, PTH receptor signaling has the potential to modulate the endocrine and auto/paracrine functions of osteocytes by regulating FGF23 through cAMP- and Wnt-dependent mechanisms.