Regulation of phosphate homeostasis by the phosphatonins and other novel mediators

Abstract

A variety of factors regulate the efficiency of phosphate absorption in the intestine and phosphate reabsorption in kidney. Apart from the well-known regulators of phosphate homeostasis, namely parathyroid hormone (PTH) and the vitamin D-endocrine system, a number of peptides collectively known as the "phosphatonins" have been recently identified as a result of the study of various diseases associated with hypophosphatemia. These factors, fibroblast growth factor 23 (FGF-23), secreted frizzled-related protein 4 (sFRP-4), fibroblast growth factor 7 (FGF-7) and matrix extracellular phosphoglycoprotein (MEPE), have been shown to play a role in the pathogenesis of various hypophosphatemic and hyperphosphatemic disorders, such as oncogenic osteomalacia, X-linked hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets, autosomal recessive hypophosphatemia and tumoral calcinosis. Whether these factors are true hormones, in the sense that they are regulated by the intake of dietary phosphorus and the needs of the organism for higher or lower amounts of phosphorus, remains to be firmly established in humans. Additionally, new information demonstrates that the intestine "senses" luminal concentrations of phosphate and regulates the excretion of phosphate in the kidney by elaborating novel factors that alter renal phosphate reabsorption.

Fig. 1

Phosphorus homeostasis in humans. Reprinted with permission [3]

Fig. 2

The interaction between parathyroid hormone and vitamin D–endocrine system in the regulation of phosphorus homeostasis

Fig. 3

Factors regulating phosphorus homeostasis in humans (FGF fibroblast growth factor, sFRP-4 secreted frizzled-related protein 4)

Fig. 4

Experimental evidence for the presence of intestinal phosphatonins that mediate changes in renal phosphate excretion following increases in luminal phosphate concentrations in the intestine. Sodium phosphate (Na P) or sodium chloride (NaCl) was infused into the duodena of rats, and fractional excretion (FE) of phosphate was measured at short intervals following the infusion (TPTX thyroparathyroidectomized)

Fig. 5

Intestinal phosphatonins mediate changes in the renal fractional excretion (FE) of phosphate following the ingestion of meals containing increased amounts of phosphate (gray hatched areas). Long-term dietary ingestion of increased amounts of phosphate is associated with increased PTH secretion and reduced 1,25- dihydroxyvitamin D synthesis. The levels of phosphatonins (PTNs) may increase following chronic increases in dietary phosphate excretion in some experimental models. Excursions in the fractional excretion of phosphate mediated by the intestinal phosphatonins still occur in the presence of an elevated baseline fractional excretion of phosphate. When phosphorus intake is curtailed, the opposite series of events occurs

Fig. 6

Relationships between changes in Pi, 1α,25(OH)₂D and FGF-23. Reprinted with permission [3]