sFRP-4: Phosphate, is there a limit?

Calcium receives considerable attention, with interest ranging from its involvement in bone density, to its relationship with cholesterol and diabetes in the development of cardiovascular disease. Its counterpart, phosphate, is less recognized, but is just as important physiologically. Total body phosphate is roughly equal to that of calcium (700 g vs. 1000 g, respectively).1,2 The bulk of both calcium and phosphate is “stored” in bone as calcium phosphate (hydroxyapatite), but significant differences exist relative to intake, absorption, and excretion. A normal Western diet (with meat and dairy products) contains 1-2 g of phosphate vs. 1 g of calcium, daily. Only 200 mg of calcium are absorbed vs. 800-900 mg of phosphate.1-3 Even less calcium is absorbed under high phosphate diets, perhaps due to the formation of unabsorbable CaPO4 complexes.2,4,5 Normally, calcium depends more on active transport than phosphate, which relies heavily on passive diffusion (paracellular transport).2 The amount absorbed roughly equals the amount excreted for both molecules. Although multiple mechanisms exist, it could be said that calcium is regulated at the level of absorption (gut), while phosphate is regulated at the level of excretion (kidney).1,2

A considerable amount of phosphate enters and leaves the blood/extracellular fluid each day. Estimates vary, but they parallel the amounts absorbed (600-800 mg). Phosphate has a multitude of functions. It enters osteoblasts to initiate mineralization and is associated with nucleotides in providing energy.6 In addition, it serves as a critical component of membranes, and is crucial as a post-translational modifier for intracellular signaling molecules.1,7 Yet, can there be too much of a good thing? Elevated serum phosphate causes metabolic acidosis, and interferes with striated muscle function.1 In addition, hyperphosphatemia (increased blood phosphate) is an independent risk factor for death in dialysis patients.2 The latter finding is of considerable interest because approximately 10% of all Americans are believed to suffer from chronic kidney disease.2

Figure 1. Phosphate in the diet is primarily taken up passively by diffusion, although some is also taken up actively by Na/P co-transporters (NPT2b). Phosphate levels are regulated at the level of excretion in the kidney. sFRP may stimulate the internalization of the NPT2a transporter, suppressing phosphate uptake.

Recently, advances in molecular biology have allowed for the identification of a number of “phosphatonins,” molecules that regulate the excretion of phosphate. Notably, there seem to be many more phosphaturic (promoting excretion) than phosphatemic (promoting retention) molecules, perhaps emphasizing the importance of limiting phosphate levels.8 One such molecule is sFRP-4 (secreted frizzled-related protein 4), a member of a small family of secreted molecules related to Frizzled receptors.9-11 Given that phosphate levels are generally regulated by the kidney, it is not surprising that sFRP-4 was also found to act at the level of the kidney.9,12 In particular, it appears to impact a specific 8-transmembrane Na/P co-transporter in renal proximal tubule cells (Figure 1). This co-transporter, termed NPT2a, internalizes both sodium and phosphate when presented with these ions in glomerular filtrate. Presumably, sFRP-4 induces the internalization of the NPT2a transporter, rendering it unavailable for phosphate uptake.9,12 The exact mechanism is unknown, but may be related to the otherwise recognized function of sFRP-4 in antagonizing Wnt signaling.9,13 sFRP-4 is currently one of two phosphatonins (FGF-23; sFRP-4), and one of four phosphaturic compounds (FGF-7; MEPE; FGF-23; sFRP-4) that are distinct from parathyroid hormone (PTH), parathyroid hormone-related peptide (PTHrP), and 1,25 diOH vitamin D. The existence of these compounds emphasizes the importance of keeping phosphate within physiologic limits.


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