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Abstract: FR-PO294

Bone-Specific Overexpression of Membrane Klotho Induces FGF23

Session Information

Category: Bone and Mineral Metabolism

  • 501 Bone and Mineral Metabolism: Basic

Authors

  • Komaba, Hirotaka, Tokai University School of Medicine, Isehara, Japan
  • Ohtsuka, Masato, Tokai University School of Medicine, Isehara, Japan
  • Ishioka, Chigusa, Tokai University School of Medicine, Isehara, Japan
  • Fajol, Abul, Tokai University School of Medicine, Isehara, Japan
  • Nakagawa, Yosuke, Tokai University School of Medicine, Isehara, Japan
  • Hamano, Naoto, Tokai University School of Medicine, Isehara, Japan
  • Ibrahim, Abd Aziz, Tokai University School of Medicine, Isehara, Japan
  • Wada, Takehiko, Tokai University School of Medicine, Isehara, Japan
  • Fukagawa, Masafumi, Tokai University School of Medicine, Isehara, Japan
Background

Klotho, either membrane-bound or soluble (or cleaved) form, acts as a coreceptor that enhances the binding affinity of FGF23 to FGF receptors (FGFRs). Soluble Klotho has been shown to potently stimulate FGF23 production in osteocytes through a yet unknown mechanism, but little is known about the role of membrane Klotho in the regulation of FGF23 production.

Methods

We generated and characterized a novel mouse strain with targeted overexpression of membrane Klotho in the osteoblast lineage, driven by the 2.3-kb Col1a1 promoter.

Results

The transgenic mice are born alive and initially indistinguishable from their control littermates, but they show growth delay and die within a few days. Overexpression of membrane Klotho in osteoblasts/osteocytes resulted in a tremendous increase in serum intact FGF23 (>1500 fold) and bone Fgf23 mRNA (>400 fold), accompanied by reduced levels of 1,25-dihydroxyvitamin D and PTH, reduced Napi2a, and elevated Cyp24a1. Treatment of these mice with an FGF-receptor blocker markedly and dose-dependently suppressed the increased bone Fgf23 expression. Using primary osteoblasts isolated from the transgenic mice, we also show that the increased Fgf23 expression during osteogenic differentiation is primarily mediated by FGFR-dependent activation of the MAPK pathway.

Conclusion

These results suggest that membrane Klotho stimulates FGF23 production in osteoblasts/osteocytes, presumably by forming a positive feedback loop mediated by the FGF23-Klotho-FGFR signaling complex. Thus, membrane Klotho expressed in bone cells functions as an amplifier of FGF23 production.