In a related experimental study, increased production of FGF23 was detected inDmp-1knockout mice with hypophosphatemia, and genetic deletion ofFgf23in such mutants resulted in similar hyperphosphatemia as that observed inFgf23single knockout mice.38Thus, hypophosphatemia inDmp-1knockout mice is though to be induced by the increased FGF23 level. == Diseases related to decreased FGF23 level == Reduced FGF23 activity can also cause diseases in humans (Table 1). dysregulation of FGF23 and Klotho is associated with vascular and skeletal anomalies owing to altered phosphate turnover. In this Review, APR-246 I summarize how the endocrine effects of bone-derived FGF23, in coordination with Klotho, can regulate systemic phosphate homeostasis, and how an inadequate balance of these molecules can lead to complications that APR-246 are caused by abnormal mineral ion metabolism. == Introduction == Phosphorus, a major mineral ion that is routinely consumed through food, is usually APR-246 associated with oxygen in the form of phosphate. Phosphate is widely distributed in the body and is an important factor in bone formation, but is also involved in cell signaling, energy metabolism, nucleic acid synthesis, and the maintenance of acidbase balance (urinary buffering).1,2The physiologic balance of phosphate is maintained by the coordinated interactions of the small intestine, bone, parathyroid gland and kidneys;38functional impairments in APR-246 any of these organs can lead to abnormal phosphate levels (Box 1). For example, in most chronic renal diseases,911impaired renal function perturbs the homeostasis of phosphate, as well as that of physiologic water, electrolytes, and mineral ion balance. == Box 1 Potential causes of serum phosphate imbalance. == Acidosis (respiratory or lactic acidosis, diabetic ketoacidosis) Alkalosis Cortical hyperostosis Drug treatment (for example amphotericin B or bisphosphonate) Glucocorticoid deficiency Impairment of growth hormone secretion (acromegaly) Impairment of thermoregulation APR-246 (hyperthermia or hypothermia) Hemolysis Infections Intestinal impairment (bowel infarction) Magnesium deficiency Milkalkali syndrome Impairment of parathyroid hormone secretion (hypoparathyroidism or pseudo-hypoparathyroidism) Phosphate-containing laxatives or enemas Renal impairment Rhabdomyolysis Sarcoidosis Trauma (for example, burns or crush injuries) Tumors (leukemia, lymphoma, bone tumors) Tumoral calcinosis Vitamin D intoxication As high as 70% of dietary phosphate can be absorbed from the upper half of the intestine and then taken up by the cells that need it; the remaining amount is mostly excreted through urine. Of particular interest, in response to the intestinal phosphate administration, phosphaturia can occur without measurable changes in plasma concentrations of phosphate and independent of parathyroid hormone, as similar responses have also been detected in parathyroidectomized animals. These observations implicate the putative existence of an intestinal phosphate sensor, which might send a hormonal signal to stimulate urinary phosphate excretion immediately after an intestinal phosphate load.12 Transepithelial phosphate transport in the intestine (through enterocytes) and in the kidney (through proximal epithelial cells) is primarily mediated by proteins in the sodium/phosphate cotransporter family (NaPi-2a, NaPi-2b and NaPi-2c) that are expressed in the apical membrane of the epithelial cells. More than 80% of the filtrated phosphate in the kidneys is reabsorbed in the proximal tubules through NaPi-2a and NaPi-2c. Various endocrine factors, including parathyroid hormone, active vitamin D metabolites and FGF23, can directly or indirectly control NaPi activities to influence systemic phosphate balance (Figure KAL2 1). In addition to parathyroid hormone and vitamin D, numerous other hormones can affect renal phosphate handling. Growth hormone, insulin, and thyroid hormone can all increase phosphate reabsorption, whereas calcitonin, glucocorticoids, and atrial natriuretic factor can decrease it, primarily by in fluencing the activity of NaPi-2a.13,14 == Figure 1. == Serum phosphate lowering effects of FGF23. FGF23 (produced in the bone) can suppress NaPi-2a and NaPi-2c cotransporters, which results in increased renal excretion of phosphate. Similarly, FGF23 can suppress renal expression of 1- hydroxylase, which leads to reduced production of calcitriol and decreased intestinal phosphate absorption, and subsequent reduced serum levels of phosphate. Among these factors, parathyroid hormone is one of the most potent regulators of phosphate metabolism. Parathyroid hormone can suppress the reabsorption of phosphate in the proximal tubules by reducing NaPi-2a and NaPi-2c activities. This reduction is achieved by internalization of NaPi proteins from the lumen side of the proximal tubular epithelial cells.15Parathyroid hormone can also mobilize phosphate from the bone into the bloodstream, possibly by enhancing osteoclastic bone resorption.16In addition, parathyroid hormone can increase the production of.