Tumoral calcinosis: a look into the metabolic mirror of phosphate homeostasis.

Phosphorus is a critical element in skeletal development, bone mineralization, membrane composition, nucleotide structure, and cellular signaling. Similar to calcium, the serum phosphorus level is maintained within a narrow range through a complex interplay between intestinal absorption, exchange with intracellular and bone storage pools, and renal tubular reabsorption. The principal organ that regulates phosphate homeostasis is the kidney. Hypophosphatemia stimulates 1,25-dihydroxyvitamin D (calcitriol) synthesis via the 25(OH)D-1 -hydroxylase in the kidney, leading to increased calcium and phosphorus absorption in the intestine and enhanced mobilization of calcium and phosphorus from bone. In addition, hypophosphatemia is a potent stimulator of an increase in maximal tubular reabsorption of phosphate. The resulting increased serum calcium inhibits PTH secretion with a subsequent increase in urinary calcium excretion and an increased tubular reabsorption of phosphate. Thus, normal serum calcium levels are maintained and serum phosphorus levels are returned to normal. PTH regulates phosphate reabsorption, but its principal function is to maintain calcium homeostasis. PTH increases urinary phosphate excretion through reduced expression of the type IIa sodiumphosphate transporter. This effect is rapid and is achieved by internalization of the transporter from the brush border membrane and enhanced lysosomal degradation (1). The classical PTH/vitamin D axis does not fully account for the complexities of phosphate homeostasis. For example, patients with inherited and acquired hypophosphatemic rickets display profound renal phosphate wasting and disruption of compensatory increases in calcitriol but maintain normal serum PTH and calcium levels. Recent advances in understanding the molecular basis of these hypophosphatemic syndromes have implicated novel regulators of phosphate homeostasis that may either act in concert or independently of the classical phosphate-homeostatic hormones. Through the study of rare syndromes of disordered phosphate homeostasis, fibroblast growth factor 23 (FGF23) excess or deficiency has emerged as a common theme. Tumor-induced osteomalacia (TIO) is a paraneoplastic syndrome of renal phosphate wasting. TIO is characterized by low serum phosphorus concentrations secondary to reduced renal reabsorption, inappropriately low calcitriol levels, but normal calcium and PTH. The biochemical derangements are accompanied by defective bone mineralization. Clinical and experimental studies have implicated the humoral factor(s) (termed “phosphatonin”) propagated by mesenchymal tumors in the profound biochemical and skeletal alterations observed in TIO (2). Efforts to identify phosphatonin were accelerated by using gene expression profiles of these tumors (3, 4). FGF23 was among the first phosphatonin candidates identified and is supported by the strongest experimental evidence. FGF23 is expressed at very low levels in normal tissue but is highly expressed in TIO tumors. Serum levels of FGF23 are markedly elevated in patients with TIO and plummet after surgical resection of the culprit tumor (5). Furthermore, the biochemical and skeletal abnormalities of transgenic mice that overexpress FGF23 mimic human TIO (6, 7). FGF23 is also implicated in the pathogenesis of two inherited renal phosphate wasting syndromes: autosomal dominant hypophosphatemic rickets (ADHR) and X-linked hypophosphatemic rickets (XLH). Missense mutations at arginine 176 or 179 of FGF23 have been identified in affected members of ADHR families (8). These mutated arginine residues prevent the degradation of FGF23, resulting in prolonged and/or enhanced FGF23 action. Amassing evidence suggests that FGF23 is central in the pathogenesis of XLH. XLH is caused by mutations in the PHEX gene (phosphateregulating gene with homologies to endopeptidases on the X chromosome), which encodes an M13 metalloprotease (9). Speculation about the function of PHEX, paired with data that implicate both an intrinsic osteoblast defect and a humoral factor in the pathogenesis of XLH, led to the hypothesis that FGF23 is either directly or indirectly regulated by PHEX. The hyp mouse, the murine homolog of XLH, has elevated serum FGF23 levels and increased FGF23 mRNA expression in the skeleton, providing support for the role of FGF23 in the pathophysiology of this disorder. Most XLH patients have elevated serum FGF23 levels, albeit to a more modest degree than TIO (5). In addition to XLH and TIO, patients with extensive fibrous dysplasia of bone that develop renal phosphate wasting exhibit elevated serum FGF23 levels that correlate with the extent of bony involvement (10). Familial tumoral calcinosis (FTC) is the metabolic opposite of TIO, XLH, and ADHR. FTC is characterized by ectopic calcification (periarticular or dermal), hyperphosphatemia owing to enhanced renal phosphate retention, and inappropriately normal or elevated calcitriol. Patients with FTC may exhibit dental defects with short bulbous roots, pulp stones, and swirled radicular dentin deposits. Given that FGF23 excess is the common molecular basis for several forms of hypophosphatemic rickets, it was temping to speculate that the molecular defect in FTC would be FGF23 deficiency. Surprisingly, the genetic defect in FTC was identified as biallelic loss-of-function mutations in the GALNT3 gene. GALNT3 encodes UDP-N-acetyl-D galactosamine: polypeptide N-acetylgalactosaminyltransferase (ppGaNAbbreviations: ADHR, Autosomal dominant hypophosphatemic rickets; FGF23, fibroblast growth factor 23; FTC, familial tumoral calcinosis; PHEX, phosphate-regulating gene with homologies to endopeptidases on the X chromosome; TIO, tumor-induced osteomalacia; XLH, X-linked hypophosphatemic rickets.