Regulation of FGF23 production and phosphate metabolism by bone–kidney interactions

Abstract

The bone-derived hormone fibroblast growth factor 23 (FGF23) functions in concert with parathyroid hormone (PTH) and the active vitamin D metabolite, 1,25(OH)2 vitamin D (1,25D), to control phosphate and calcium homeostasis. A rise in circulating levels of phosphate and 1,25D leads to FGF23 production in bone. Circulating FGF23 acts on the kidney by binding to FGF receptors and the co-receptor α-Klotho to promote phosphaturia and reduce circulating 1,25D levels. Various other biomolecules that are produced by the kidney, including lipocalin-2, glycerol 3-phosphate, 1-acyl lysophosphatidic acid and erythropoietin, are involved in the regulation of mineral metabolism via effects on FGF23 synthesis in bone. Understanding of the molecular mechanisms that control FGF23 synthesis in the bone and its bioactivity in the kidney has led to the identification of potential targets for novel interventions. Emerging approaches to target aberrant phosphate metabolism include small molecule inhibitors that directly bind FGF23 and prevent its interactions with FGF receptors and α-Klotho, FGF23 peptide fragments that act as competitive inhibitors of intact FGF23 and small molecule inhibitors of kidney sodium-phosphate cotransporters. In this Review, the authors discuss the mineral-related factors and kidney-derived molecules that regulate osteocyte FGF23 production in health and disease. They also highlight potential approaches to the treatment of FGF23-related disorders of mineral metabolism that target key bone–kidney interactions.