Pediatr Nephrol (2008) 23:1203–1210 1205 Fig. 3 Factors regulating phosphorus homeostasis in humans (FGF fibroblast growth factor, sFRP-4 secreted frizzled-related protein 4) (Fig. 3) [8]. Recent findings from our laboratory suggest that unique intestinal factors (“intestinal phosphatonins”), released by increases in intestinal luminal phosphate concentrations, alter the renal reabsorption of phosphate (Figs. 4 and 5) [9]. It is likely that these intestinal phosphatonins mediate the short-term changes in the fractional excretion of phosphate observed after ingestion of a meal, and it is likely that they play a role in the short- term adaptation to changes in dietary phosphate. On the other hand, long-term changes in dietary phosphate may be associated with changes in PTH, 1,25-dihydroxyvitamin D and the phosphatonins (see below). The phosphatonins and disorders of phosphate homeostasis in humans: The term “phosphatonin” was coined in 1994 to describe a circulating phosphaturic factor present in the serum of patients with oncogenic or tumor-induced osteomalacia (TIO) [10, 11]. Cai et al. described a patient with TIO in whom the biochemical phenotype of hypo- phosphatemia, renal phosphate wasting, reduced 1α,25- dihydroxyvitamin D (1α,25(OH)2D) concentrations and the 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 phos- phate 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 osteomalacia resolved after removal of the tumor [10, 11]. X-linked hypophosphatemic rickets (XLH) [12], autosomal dominant hypophosphatemic rickets (ADHR) [13], and autosomal recessive hypophosphatemia (ARHP) [14] are disorders that are phenotypically similar to TIO and which demonstrate the presence of a circulating factor responsible for hypophosphatemia and renal phosphate wasting [14– 17]. Conversely, concentrations of one of the phosphato- nins, fibroblast growth factor 23, are reduced in patients with tumoral calcinosis (TC), a disorder characterized by hyperphosphatemia, reduced fractional excretion of phos- phate and deposits of calcium phosphate in soft tissues [18– 24]. Several proteins, such as fibroblast growth factor-23 (FGF-23), secreted frizzled-related protein (sFRP-4), matrix extracellular phosphoglycoprotein (MEPE) and fibroblast growth factor-7 (FGF-7) have been identified as potential phosphatonins and probably play a role in the pathogenesis of some of these disorders [3, 14, 16, 17, 25–28]. Table 1 summarizes the pathophysiology of some of these hypo- phosphatemic and hyperphosphatemic disorders. A more detailed discussion of each of these peptides and their physiology and pathophysiology follows. The biology of phosphatonins Fibroblast growth factor-23: FGF-23 is a secreted, circu- lating, 32-kDa protein that is predominantly expressed in osteocytes in the bone and in the endothelial cells that line the venous sinusoids of bone marrow and the thymus [29].