title: Interleukin-1-induced acute bone resorption facilitates the secretion of fibroblast growth factor 23 into the circulation.
abstract: Fibroblast growth factor 23 (FGF23), a central regulator of phosphate and vitamin D metabolism, is mainly produced by osteocytes in bone and exerts its effects on distant organs. Despite its endocrine function, the mechanism controlling serum FGF23 levels is not fully understood. Here we tested the hypothesis that osteoclastic bone resorption may play a role in regulating circulating levels of FGF23, using a mouse model where injections of interleukin (IL)-1β into the subcutaneous tissue over the calvaria induced rapid bone resorption. A significant amount of FGF23 was detected in the extracts from mouse bones, which supports the idea that FGF23 stays in bone for a while after its production. IL-1β-induced bone resorption was associated with elevated serum FGF23 levels, an effect abolished by pre-treatment with pamidronate. Fgf23 expression was not increased in either the calvariae or tibiae of IL-1β-injected mice, which suggests that IL-1β facilitated the entry of FGF23 protein into circulation by accelerating bone resorption rather than increasing its gene expression. The direct effect of IL-1β on bone was confirmed when it increased FGF23 levels in the conditioned media of mouse calvariae in organ culture. Repeated treatment of the cultured calvariae with IL-1β led to a refractory phase, where FGF23 was not mobilized by IL-1β anymore. Consistent with the in vivo results, treatment with IL-1β failed to increase Fgf23 mRNA in isolated primary osteocytes and osteoblasts. These results suggest that FGF23 produced by osteocytes remains in bone, and that rapid bone resorption facilitates its entry into the bloodstream.
authors.affiliation: Department of Bone and Mineral Research, Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Osaka, 594-1101, Japan.
authors.forename: Miwa
authors.initials: M
authors.lastname: Yamazaki
authors.forename: Masanobu
authors.initials: M
authors.lastname: Kawai
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Miyagawa
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Ohata
authors.forename: Kanako
authors.initials: K
authors.lastname: Tachikawa
authors.forename: Saori
authors.initials: S
authors.lastname: Kinoshita
authors.forename: Jin
authors.initials: J
authors.lastname: Nishino
authors.forename: Keiichi
authors.initials: K
authors.lastname: Ozono
authors.forename: Toshimi
authors.initials: T
authors.lastname: Michigami
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001862:Bone Resorption / Q000188:drug therapy; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007375:Interleukin-1 / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism; D010011:Osteocytes / Q000187:drug effects / Q000378:metabolism; D012886:Skull / Q000187:drug effects / Q000378:metabolism
chemical_list: C000717428:Fgf23 protein, mouse; D007375:Interleukin-1; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23