Klotho expression in long bones regulates FGF23 production during renal failure

Area of Science:

• Endocrinology
• Nephrology
• Bone Biology

Background:

• Fibroblast growth factor 23 (FGF23) levels rise in kidney disease, linked to poor outcomes.
• Membrane-bound Klotho, a FGF23 coreceptor, is expressed in bone cells.
• A potential autocrine feedback loop involving bone Klotho and FGF23 is proposed.

Purpose of the Study:

• To investigate the role of bone-derived Klotho in regulating FGF23 production during renal failure.
• To elucidate the autocrine feedback mechanism of Klotho in bone cells under uremic conditions.

Main Methods:

• Targeted deletion of Klotho in long bones of mice (Prx1-Cre;KL mice).
• Induction of renal failure using adenine diet and 5/6 nephrectomy models.
• Analysis of FGF23, parathyroid hormone, vitamin D, calcium, and gene expression in uremic mice.
• In vitro studies on FGF23-treated bone cells with and without Klotho.

Main Results:

• Mice lacking Klotho in long bones showed impaired FGF23 induction during renal failure.
• These mice exhibited altered mineral metabolism, including lower FGF23 and PTH, and higher vitamin D and calcium.
• Bone cells required Klotho for FGF23 mRNA upregulation and ERK phosphorylation in response to FGF23.

Conclusions:

• Klotho expression in long bone osteoblasts/osteocytes is critical for FGF23 production during renal failure.
• A novel autocrine feedback loop exists where bone Klotho senses the need for FGF23.
• This finding highlights a new regulatory pathway in the pathogenesis of kidney disease-mineral and bone disorder.