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FGF23 is an endocrine FGF produced by osteocytes, which increases excretion of phosphate and suppresses the production of 1,25 (OH) 2D. Excessive action of FGF23 causes various forms of hypophosphatemic rickets/osteomalacia, while the loss of function of FGF23 results in the condition called familial hyperphosphatemic tumoral calcinosis. 1,25 (OH) 2D stimulates the production of FGF23, and the interaction between FGF23 and 1,25 (OH) 2D plays a central role in mineral homeostasis. In addition to the its roles in mineral homeostasis, recent studies have suggested the direct action of FGF23 on osteoblasts and chondrocytes.

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) , an autosomal recessive disorder first identified in a large Bedouin tribe, is characterized by hypophosphatemia secondary to renal inorganic phosphate (Pi) wasting, resulting in increased serum1,25-dihydroxyvitamin D3 concentrations with associated intestinal calcium hyperabsorption, hypercalciuria, rickets, and osteomalacia. Recent studies identified several mutations in the NaPi-2c/NPT2c transporter gene (SLC34A3) as the cause of HHRH. The fact that HHRH is caused by NaPi-2c loss-of-function mutations is compatible with the HHRH phenotype and the prevailing view of renal Pi regulation. The NaPi-2c mutants in HHRH show defective processing and stability.