Soluble Klotho causes hypomineralization in Klotho-deficient mice. Issue 3 (June 2018)

• Record Type: Journal Article
• Authors: Minamizaki, Tomoko; Konishi, Yukiko; Sakurai, Kaoru; Yoshioka, Hirotaka; Aubin, Jane E; Kozai, Katsuyuki; Yoshiko, Yuji
• Is Part Of: Journal of endocrinology. Volume 237:Issue 3(2018)
• Page Start: 285
• Page End: 300
• Publication Date: 2018-06
• Subjects: FGF23 -- Klotho -- Phex -- kl/kl mice; Endocrinology -- Periodicals; 616.4005
• DOI: 10.1530/JOE-17-0683
• Languages: English
• ISSNs: 0022-0795

Abstract

Abstract : The type I transmembrane protein αKlotho (Klotho) serves as a coreceptor for the phosphaturic hormone fibroblast growth factor 23 (FGF23) in kidney, while a truncated form of Klotho (soluble Klotho, sKL) is thought to exhibit multiple activities, including acting as a hormone, but whose mode(s) of action in different organ systems remains to be fully elucidated. FGF23 is expressed primarily in osteoblasts/osteocytes and aberrantly high levels in the circulation acting via signaling through an FGF receptor (FGFR)-Klotho coreceptor complex cause renal phosphate wasting and osteomalacia. We assessed the effects of exogenously added sKL on osteoblasts and bone using Klotho-deficient ( kl/kl ) mice and cell and organ cultures. sKL induced FGF23 signaling in bone and exacerbated the hypomineralization without exacerbating the hyperphosphatemia, hypercalcemia and hypervitaminosis D in kl/kl mice. The same effects were seen in rodent bone models in vitro, in which we also detected formation of a sKL complex with FGF23-FGFR and decreased Phex (gene responsible for X-linked hypophosphatemic rickets (XLH)/osteomalacia) expression. Further, sKL-FGF23-dependent hypomineralization in vitro was rescued by soluble PHEX. These data suggest that exogenously added sKL directly participates in FGF23 signaling in bone and that PHEX is a downstream effector of the sKL-FGF23-FGFR axis in bone.