Study of the FGF23-soluble Klotho axis in bone and dental diseases.

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We found that FG23, a phosphaturic factor, inhibits bone formation even though membrane Klotho (mKL), a coreceptor for FGF23 is not expressed in bone. It is known that mKL is cleaved and circulated as soluble KL (sKL). We confirmed that sKL supports the FGF23 effects on bone. Among FGF family members expressed in bone, FGF23, transcriptionally activated by 1,25(OH)2D3, stimulated transient activation of ERK1/2 only in mature steoblasts/osteocytes. This signaling downregulated Phex, with the resultant increase in the accumulation of ASARM peptide in bone. Administration of ASARM peptide decreased bone mineralization without affecting osteoblast proliferation and differentiation. These data describe a novel mechanism by which FGF23 regulates bone formation.