title: Parathyroid hormone receptor signaling in osteocytes increases the expression of fibroblast growth factor-23 in vitro and in vivo.
abstract: 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 osteocyte-derived 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-caPTHR1 mice; however, plasma Pi or renal Pi reabsorption is not altered. Furthermore, the FGF23 receptor complex comprising FGFR1 and KLOTHO is expressed in osteoblastic cells; and FGFR1, GALNT3, as well as downstream targets of FGF23 signaling, are increased in osteocytes but not in osteoblasts from DMP1-caPTHR1 mice. 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.
authors: Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN 46022, USA. yumie@yuhs.ac
authors: Yumie
authors: Y
authors: Rhee
authors: Nicoletta
authors: N
authors: Bivi
authors: Emily
authors: E
authors: Farrow
authors: Virginia
authors: V
authors: Lezcano
authors: Lilian I
authors: LI
authors: Plotkin
authors: Kenneth E
authors: KE
authors: White
authors: Teresita
authors: T
authors: Bellido
mesh_terms: D000042:Absorption; D000818:Animals; D001842:Bone and Bones / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000097:blood / Q000235:genetics*; D007668:Kidney / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D010011:Osteocytes / Q000378:metabolism*; D010710:Phosphates / Q000097:blood; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: C513308:Dmp1 protein, mouse; D016326:Extracellular Matrix Proteins; C000717428:Fgf23 protein, mouse; D010710:Phosphates; D012333:RNA, Messenger; D044168:Receptor, Parathyroid Hormone, Type 1; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23