In addition, the FGF23–Klotho system also regulates vitamin D metabolism, which is an important factor that regulates the homeostasis of minerals such as calcium, phosphorus, and magnesium. The FGF23–Klotho system suppresses sodium-phosphate cotransporters (NaPi2 family proteins) in proximal tubular epithelial cells in the kidney to induce urinary phosphate wasting. Aberrations in FGF23, FGFR, or Klotho structure or expression result in dysregulation of serum phosphate levels in experimental animal models and human diseases. FGF23 binds the membrane-bound Klotho–FGF receptor complex with much higher affinity than the FGF receptor (FGFR) alone to generate downstream signaling events. Phosphate homeostasis is maintained by FGF23 derived from bones and the kidney-derived cofactor Klotho. Most phosphorus in the body is sequestered in mineralized bone tissue and teeth. Phosphorus (usually as phosphate) is an essential nutrient used for enzyme activation and the synthesis of adenosine triphosphate and other biomolecules. The purpose of this review is to discuss experimental findings regarding Na+-independent inorganic phosphate transporters and summarize their roles in Pi homeostasis, cancers and other diseases, such as osteoarthritis, and in processes such as VC. This Pi H+-dependent transport has a fundamental role in the proliferation and migratory capacity of MDA-MB-231 cells. Recently, it was demonstrated that breast cancer cells (MDA-MB-231) respond to high Pi concentration (2 mM) by decreasing Na+-dependent Pi transport activity concomitant with an increase in Na+-independent (H+-dependent) Pi transport. According to the growth rate hypothesis, cancer cells require more phosphate than healthy cells due to their rapid growth rates. Na+-independent Pi transporters have been identified and biochemically characterized in vascular smooth muscle cells (VSMCs), chondrocytes, and matrix vesicles, and their involvement in mineral deposition in the extracellular microenvironment has been suggested. Hyperphosphatemia is a risk factor for mineral deposition, the development of diseases such as osteoarthritis, and vascular calcifications (VCs).
This transporter assists in the absorption of Pi by intestinal cells and renal proximal tubule cells and in the reabsorption of Pi by osteoclasts and capillaries of the blood–brain barrier (BBB). However, a new type of sodium-independent Pi transporter has been identified. Mammalian cells depend on Na+/Pi cotransporters for Pi absorption, which have been well studied. In healthy mammals, extracellular Pi is maintained within a narrow concentration range of 0.70 to 1.55 mM. Inorganic phosphate (Pi) is an essential nutrient for the maintenance of cells. The aim of this review is to discuss our current knowledge of the processes and role of the intestine in phosphate homeostasis and to provide evidence that this organ could be targeted for the treatment of hypophosphatemia and hyperphosphatemia. Interestingly, studies using NaPi-IIb knockout mice with adenine-induced CKD show only partial attenuation of hyperphosphatemia, suggesting that an additional sodium-independent pathway is involved in phosphate absorption. It may also be involved in the sensing of dietary phosphate composition and the release of hormonal factors that modulate renal phosphate reabsorption to achieve phosphate balance. Our current understanding is that the intestinal type II sodium phosphate cotransporter, NaPi-IIb, plays a significant role in absorption. Phosphate homeostasis is maintained by the crosstalk between intestinal phosphate absorption and renal phosphate excretion however, relatively little is known about the mechanisms of intestinal phosphate transport.
Results from retrospective studies suggest that small increases in serum phosphate concentration, within the normal or near-normal range, also correlate with increased cardiovascular morbidity and mortality and have led to the suggestion that detection and preventative treatment of positive phosphate balance is important in healthy individuals as well as in those with CKD. Hyperphosphatemia is a serious complication of late-stage chronic kidney disease (CKD), contributing to the increased cardiovascular morbidity and mortality seen in this patient group.