| FGF‑23 is an osteocyte‑derived endocrine member of the FGF19 subfamily that plays a central role in systemic phosphate and vitamin D regulation by targeting the kidney and parathyroid gland through a Klotho‑dependent FGFR1c signaling module, directly linking skeletal mineral sensing to renal phosphate handling and steroid hormone metabolism. The mature FGF‑23 protein features the conserved FGF β‑trefoil core and a C‑terminal RXXR proteolytic motif, and it forms a high-affinity complex with FGFR1c only in the presence of the single-pass co-receptor α‑Klotho, conferring endocrine specificity to Klotho-expressing tissues such as renal tubules and parathyroid cells. Upon engaging FGFR1c–Klotho complexes in the kidney, FGF‑23 activates canonical FGF signaling pathways involving FRS2 and ERK1/2, resulting in reduced expression and apical localization of the sodium–phosphate cotransporters NaPi‑2a and NaPi‑2c and in suppression of Cyp27b1 with concurrent stimulation of Cyp24a1 in proximal tubules, which together diminish tubular phosphate reabsorption and lower circulating 1,25‑dihydroxyvitamin D levels while enhancing its catabolism. These actions decrease intestinal phosphate absorption and promote urinary phosphate excretion, establishing a bone–kidney feedback loop wherein 1,25‑dihydroxyvitamin D and phosphate stimulate FGF‑23 synthesis in bone, while FGF‑23 constrains 1α‑hydroxylase and phosphate reabsorption in the kidney to prevent phosphate and vitamin D excess. In distal tubules, FGF‑23 signaling increases calcium and sodium retention by upregulating TRPV5‑mediated Ca²⁺ reabsorption and NCC‑dependent NaCl transport, and supports proper PTH responsiveness, demonstrating that FGF‑23 orchestrates broader mineral and volume homeostasis within the nephron. Genetic or acquired FGF‑23 excess is a key driver of hypophosphatemic disorders, including autosomal dominant hypophosphatemic rickets, X‑linked hypophosphatemia, and tumor‑induced osteomalacia, all characterized by renal phosphate wasting, low 1,25‑dihydroxyvitamin D, rickets/osteomalacia, and defective bone mineralization. In contrast, loss‑of‑function mutations in FGF23 or Klotho lead to hyperphosphatemia, elevated 1,25‑dihydroxyvitamin D, and widespread soft tissue calcification. The main physiological function of FGF‑23 is suppression of renal 1α‑hydroxylase and vitamin D hormone production, with phosphaturic effects serving to complement protection against phosphate overload. In chronic kidney disease, FGF‑23 levels rise early in response to reduced phosphate clearance and contribute to the suppression of 1,25‑dihydroxyvitamin D and the development of secondary hyperparathyroidism, while sustained FGF‑23 elevation is linked to left ventricular hypertrophy and increased cardiovascular risk, establishing FGF‑23 as both a mechanistic effector and a clinically relevant biomarker throughout CKD progression. |
