Klotho (KL) is a type-I-membrane protein required for FGF23 to bind FGFR1 and modulate mineral ion homeostasis. Loss of either KL or FGF23 results in severe mineralisation defects. We recently found that membrane KL is expressed in osteoblasts and osteocytes, which are major sites of FGF23 syntheses. To investigate the role of bone-specific KL in mineral ion homeostasis and the progression of bone mineralisation defects in chronic kidney disease, we generated a mouse strain with limb-specific KL deletion using Prx1-Cre. No differences were seen in body weight, serum phosphate, FGF23, PTH, calcitriol or cortical bone volume between KLfl/fl and Prx1-Cre;KLfl/fl mice at 6, 16 or 24 weeks of age. However, as early as 6 weeks of age Prx1-Cre;KLfl/fl mice had lower trabecular bone volume and connectivity than KLfl/fl mice. To challenge the mice, we induced chronic kidney failure by feeding mice adenine diet for 8 weeks. At 16 weeks of age, all mice fed adenine diet had reduced body weight, kidney atrophy, high urea concentrations (80120 pg/ml) and hyperphosphataemia, confirming the induction of renal failure. No differences in these parameters were seen between adenine fed KLfl/fl and Prx1-Cre;KLfl/fl mice. However, limbs of adenine fed Prx1-Cre;KLfl/fl mice did not respond with an increase in Fgf23 mRNA expression that is characteristic of renal failure and was observed in adenine fed KLfl/fl mice. As such, adenine fed Prx1-Cre;KLfl/fl had significantly lower serum iFGF23 levels than adenine fed KLfl/fl mice, higher expression of renal 1α-hydroxylase, hypercalcaemia and severe kyphosis. To validate the results, findings were confirmed in 5/6 NTX Prx1-Cre;KLfl/fl mice. Therefore, our data is the first to show that limb-specific KL plays an important role in regulating mineral ion homeostasis and more importantly FGF23 production. This novel data suggests that Klotho expression in bone cells provides a sensor for the need of FGF23.
Disclosure: Dod Department of Defense (PR120411).
Canadian Institutes of Health Research Postdoctoral Fellowship.
16 - 20 May 2015
European Society of Endocrinology