Klotho expression in long bones regulates FGF23 production during renal failure.
Circulating levels of bone-derived fibroblast growth factor 23 (FGF23) increase early during acute and chronic kidney disease and are associated with adverse outcomes. Membrane-bound Klotho acts as a permissive coreceptor for FGF23, and its expression was recently found in osteoblasts/osteocytes. We hypothesized that Klotho in bone cells is part of an autocrine feedback loop that regulates FGF23 expression during renal failure. Thus, we induced renal failure in mice with targeted deletion of Klotho in long bones. Uremic wild-type (KLfl/fl) and knockout (Prx1-Cre;KLfl/fl) mice both responded with reduced body weight, kidney atrophy, hyperphosphatemia, and increased bone turnover. Importantly, long bones ofPrx1-Cre;KLfl/flmice but not their axial skeleton failed to increaseFGF23expression as observed in uremicKLfl/flmice. Consequently,Prx1-Cre;KLfl/flmice had significantly lower serum FGF23 and parathyroid hormone levels, and higher renal 1-α-hydroxylase expression, serum 1,25-dihydroxyvitamin D, and calcium levels thanKLfl/flmice. These results were confirmed in two independent models of renal failure, adenine diet induced and 5/6 nephrectomy. Moreover, FGF23-treated bone cells required Klotho to increaseFGF23mRNA and ERK phosphorylation. In summary, our novel findings show that Klotho in bone is crucial for inducing FGF23 production upon renal failure. We propose the presence of an autocrine feedback loop in which Klotho senses the need for FGF23.-Kaludjerovic, J., Komaba, H., Sato, T., Erben, R. G., Baron, R., Olauson, H., Larsson, T. E., Lanske, B. Klotho expression in long bones regulates FGF23 production during renal failure.
Division of Bone and Mineral Research, Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, Massachusetts, USA.
Jovana
J
Kaludjerovic
Division of Bone and Mineral Research, Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, Massachusetts, USA.
Hirotaka
H
Komaba
Division of Bone and Mineral Research, Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, Massachusetts, USA.
Tadatoshi
T
Sato
Unit of Physiology, Pathophysiology, and Experimental Endocrinology, University of Veterinary Medicine, Vienna, Austria.
Reinhold G
RG
Erben
Division of Bone and Mineral Research, Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, Massachusetts, USA.|Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Roland
R
Baron
Division of Renal Medicine, Department of Clinical Sciences, Intervention, and Technology, Karolinska Institutet, Stockholm, Sweden.
Hannes
H
Olauson
Division of Renal Medicine, Department of Clinical Sciences, Intervention, and Technology, Karolinska Institutet, Stockholm, Sweden.
Tobias E
TE
Larsson
Division of Bone and Mineral Research, Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, Massachusetts, USA; beate_lanske@hsdm.harvard.edu.|Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Beate
B
Lanske
D000818:Animals; D001842:Bone and Bones / Q000378:metabolism; D002117:Calcitriol / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D005966:Glucuronidase / Q000172:deficiency / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism*; D000090265:Klotho Proteins; D018345:Mice, Knockout; D010006:Osteoblasts / Q000378:metabolism; D010281:Parathyroid Hormone / Q000235:genetics; D010710:Phosphates / Q000378:metabolism; D051437:Renal Insufficiency / Q000378:metabolism*
C000717428:Fgf23 protein, mouse; D010281:Parathyroid Hormone; D010710:Phosphates; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D005966:Glucuronidase; D000090265:Klotho Proteins; D002117:Calcitriol; D002118:Calcium
bone metabolism; chronic kidney disease; fibroblast growth factor 23