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Interleukin-1-induced acute bone resorption facilitates the secretion of fibroblast growth factor 23 into the circulation

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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.

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Acknowledgments

This work was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Science, and Culture of Japan (to M.Y. and T.M.), Ministry of Health, Labour, and Welfare of Japan (to T.M.), and funds from Novo Nordisk Pharma. Ltd. (to T.M.).

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All authors have no conflicts of interest.

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Authors and Affiliations

  1. Department of Bone and Mineral Research, Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Osaka, 594-1101, Japan

    Miwa Yamazaki, Masanobu Kawai, Kazuaki Miyagawa, Yasuhisa Ohata, Kanako Tachikawa, Saori Kinoshita, Jin Nishino & Toshimi Michigami

  2. Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871, Japan

    Yasuhisa Ohata & Keiichi Ozono

  3. Department of 1st Oral Surgery, Osaka University Graduate School of Dentistry, Suita, Osaka, 565-0871, Japan

    Kazuaki Miyagawa & Jin Nishino

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  1. Miwa Yamazaki
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Correspondence to Toshimi Michigami.

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Yamazaki, M., Kawai, M., Miyagawa, K. et al. Interleukin-1-induced acute bone resorption facilitates the secretion of fibroblast growth factor 23 into the circulation. J Bone Miner Metab 33, 342–354 (2015). https://doi.org/10.1007/s00774-014-0598-2

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  • DOI: https://doi.org/10.1007/s00774-014-0598-2

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