PHEX protein in the parathyroid gland contributes to phosphate sensing.

Context: Loss-of-function variants in the PHEX gene cause X-linked hypophosphatemia (XLH) with inappropriate secretion of fibroblast growth factor (FGF) 23. The PHEX protein is therefore predicted to be involved in the phosphate (Pi)-sensing mechanism in mature osteocytes. The parathyroid glands sense short-term fluctuations in serum Pi levels and secrete parathyroid hormone (PTH) accordingly. However, the precise mechanisms for Pi sensing in the parathyroid gland have not been elucidated.

Objective: To clarify the involvement of PHEX in phosphate sensing in the parathyroid glands, PTH reactions after Pi loading were retrospectively compared between patients with XLH and those with tumor-induced osteomalacia (TIO).

Methods: Serum Pi, intact PTH (iPTH) and albumin-corrected serum calcium (cCa) levels at 1 hour after oral phosphate administration at doses ranging from 300 mg to 1,500 mg were analyzed. The trend of iPTH in each participant was compared between XLH and TIO.

Results: Six XLH patients and 13 TIO patients were included. The serum Pi level significantly increased after the oral Pi load, whereas the serum cCa level was stable. The slope of the scatter plot of iPTH (pg/mL) versus Pi (mg/dL) after the oral Pi load for each patient was 41.4 (median) in XLH, which was significantly greater than the 7.1 in TIO (p = 0.034).

Conclusion: iPTH increased in accordance with Pi levels, with a greater slope observed in XLH than in TIO after oral Pi loading. This finding suggests that PHEX in the parathyroid glands might also determine the serum Pi-sensing threshold and mediate PTH secretion in the case of abrupt fluctuations in serum Pi levels, which may explain the high prevalence of secondary and tertiary hyperparathyroidism in patients with XLH.