Fibroblast growth factor 23 (FGF23), produced by osteocytes and osteoblasts in response to high phosphate and high 1,25-dihydroxyvitamin D, acts on the kidney co-receptor Klotho/FGFR1. The net effect of FGF23 on phosphate metabolism involves two complementary renal actions. Which correctly describes both?

• A FGF23 increases NaPi-2a and NaPi-2c cotransporters in the proximal tubule (increasing phosphate reabsorption) AND stimulates CYP27B1 to increase 1,25(OH)₂D
• B FGF23 stimulates PTH secretion from the parathyroid glands AND inhibits renal calcium reabsorption in the distal tubule
• C FGF23 reduces NaPi-2a and NaPi-2c expression (causing phosphaturia) AND inhibits CYP27B1 (1-alpha-hydroxylase) while stimulating CYP24A1 (24-hydroxylase) to reduce active vitamin D levels ✓
• D FGF23 increases renal phosphate reabsorption but reduces intestinal phosphate absorption via downregulating NaPi-2b in the duodenum

Explanation

FGF23 acts on proximal tubular cells via Klotho/FGFR1 to simultaneously: (1) downregulate sodium-phosphate cotransporters NaPi-2a (SLC34A1) and NaPi-2c (SLC34A3) at the apical brush border, reducing phosphate reabsorption and causing phosphaturia; and (2) inhibit CYP27B1 (1α-hydroxylase) while stimulating CYP24A1 (24-hydroxylase), thus reducing 1,25(OH)₂D synthesis and accelerating its catabolism. Lowered 1,25(OH)₂D then reduces intestinal phosphate and calcium absorption. This dual action constitutes a powerful 'phosphatonin' feedback loop. Loss-of-function FGF23 mutations or Klotho deficiency cause tumoral calcinosis (hyperphosphatemia); gain-of-function FGF23 or its excess causes X-linked hypophosphatemia.

Reference: Guyton & Hall, Textbook of Medical Physiology, 14th ed.

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