FGF23 is a phosphatonin secreted by osteocytes in response to elevated phosphate. In X-linked hypophosphatemia (XLH), PHEX gene mutations cause elevated FGF23. The mechanism by which elevated FGF23 causes hypophosphatemia is:
- A FGF23 activates FGFR1-Klotho complexes in renal tubules, suppressing NaPi-IIa and NaPi-IIc co-transporters, reducing phosphate reabsorption ✓
- B FGF23 directly inhibits 1-alpha-hydroxylase in osteoblasts, preventing calcitriol synthesis
- C FGF23 suppresses PTH secretion from the parathyroid gland, removing phosphaturic drive
- D FGF23 induces osteoclast-mediated bone resorption releasing hydroxyapatite phosphate into circulation where it is lost by tubular overflow
Explanation
FGF23 acts on renal proximal tubular cells by binding FGFR1 (requiring co-receptor alpha-Klotho). This signalling suppresses expression of sodium-phosphate co-transporters NaPi-IIa (SLC34A1) and NaPi-IIc (SLC34A3) on the brush border, reducing phosphate reabsorption and causing phosphaturia with hypophosphatemia. Additionally, FGF23 inhibits renal 1-alpha-hydroxylase (CYP27B1) and stimulates 24-hydroxylase (CYP24A1), reducing active vitamin D (calcitriol) levels, which further impairs intestinal phosphate absorption. This dual mechanism (renal wasting + reduced 1,25-D) causes rickets/osteomalacia in XLH.
Reference: Harper's Illustrated Biochemistry, 32nd ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.