A basic study on FGF23 for molecular targeted therapy of bone/tooth diseases

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Fibroblast growth factor 23 (FGF23) acts as a phosphaturic hormone upon 1α, 25-dihydroxyvitamin D_3 (1,25(OH)_2D_3) stimulation, and the truncated form (sKL) of Klotho, a coreceptor for FGF23 in kidney, is released into the circulation. Here, we show that an intravenous injection of sKL rapidly increases ERK phosphorylation as FGF23 signaling in bone but not in kidney in mice, when preloaded with 1,25(OH)_2D_3. The unique activity of sKL in bone is mimicked in Klotho-deficient mutant (kl/kl) mice, in spite of the kl/kl high serum concentrations of phosphate, calcium, 1,25(OH)_2D_3 and FGF23. These mice exhibit selective accumulation of FGF23 and sKL and subsequent hypomineralization in parietal bone, without changes in serum parameters examined. sKL in serum is necessary for complex formation with FGF23 and the corresponding hypomineralization effects in osteoblast/osteocyte cultures, when FGF23 levels are increased by 1,25(OH)_2D_3. These data define a novel bone-kidney axis in which sKL acts as a cofactor for FGF23 in parietal bone, and the unique bone milieu mediates the local actions of FGF23.