Soluble Klotho causes hypomineralization in Klotho-deficient mice

Minamizaki Tomoko

Konishi Yukiko

Sakurai Kaoru

Yoshioka Hirotaka

Aubin Jane E.

Kozai Katsuyuki

Yoshiko Yuji

Journal of Endocrinology

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.

FGF23

Klotho

Phex

kl/kl mice

Medical sciences [ 490 ]

eng

Society for Endocrinology

This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Endocrinology, copyright © Society for Endocrinology after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1530/JOE-17-0683. This is not the published version. Please cite only the published version. この論文は出版社版でありません。引用の際には出版社版をご確認、ご利用ください。

[ISSN] 0022-0795

[ISSN] 1479-6805

[DOI] 10.1530/JOE-17-0683

[PMID] 29632215

[DOI] https://doi.org/10.1530/JOE-17-0683