Phosphatonins: From Discovery to Therapeutics - Oct 2022
Endocr Pract . 2022 Oct 6;S1530-891X(22)00625-5. doi: 10.1016/j.eprac.2022.09.007
Kittrawee Kritmetapak 1 , Rajiv Kumar 2
Phosphate is crucial for cell signaling, energy metabolism, nucleotide synthesis, and bone mineralization. The gut-bone-parathyroid-kidney axis is influenced by parathyroid hormone (PTH), 1,25-dihydroxyvitamin D (1,25(OH)2D), and phosphatonins, and facilitates maintenance of phosphate homeostasis. Phosphatonins including fibroblast growth factor 23 (FGF23), secreted frizzled-related protein 4 (sFRP4), matrix extracellular phosphoglycoprotein (MEPE), and fibroblast growth factor 7 (FGF7) play a pathogenic role in several hypophosphatemic disorders. Excess FGF23 inhibits sodium-dependent phosphate cotransporters (NaPi-2a and NaPi-2c), resulting in hyperphosphaturia and hypophosphatemia. Additionally, FGF23 suppresses 1,25(OH)2D synthesis in the proximal renal tubule, and thus it indirectly inhibits intestinal phosphate absorption. Disorders of FGF23-related hypophosphatemia include X-linked hypophosphatemia (XLH), autosomal dominant hypophosphatemic rickets (ADHR), autosomal recessive hypophosphatemic rickets (ARHR), fibrous dysplasia/McCune-Albright syndrome, and tumor-induced osteomalacia (TIO). Complications of conventional therapy with oral phosphate and vitamin D analogs comprise gastrointestinal distress, hypercalcemia, nephrocalcinosis, and secondary/tertiary hyperparathyroidism. In both children and adults with XLH and TIO, the anti-FGF23 antibody burosumab exhibits a favorable safety profile and is associated with healing of rickets in affected children and improvement of osteomalacia in both children and adults. This review summarizes current knowledge regarding the phosphate homeostasis, phosphatonin pathophysiology, and clinical implications of FGF23-related hypophosphatemic disorders, with specific focus on burosumab treatment.
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Vitamin D and Phosphate Interactions in Health and Disease - March 2022, book chapter
DOI: 10.1007/978-3-030-91623-7_5 10 pages
Nuraly S. Akimbekov, Ilya Digel, Dinara K. Sherelkhan & Mohammed S. Razzaque
Vitamin D plays an essential role in calcium and inorganic phosphate (Pi) homeostasis, maintaining their optimal levels to assure adequate bone mineralization. Vitamin D, as calcitriol (1,25(OH)2D), not only increases intestinal calcium and phosphate absorption but also facilitates their renal reabsorption, leading to elevated serum calcium and phosphate levels. The interaction of 1,25(OH)2D with its receptor (VDR) increases the efficiency of intestinal absorption of calcium to 30–40% and phosphate to nearly 80%. Serum phosphate levels can also influence 1,25(OH)2D and fibroblast growth factor 23 (FGF23) levels, i.e., higher phosphate concentrations suppress vitamin D activation and stimulate parathyroid hormone (PTH) release, while a high FGF23 serum level leads to reduced vitamin D synthesis. In the vitamin D-deficient state, the intestinal calcium absorption decreases and the secretion of PTH increases, which in turn causes the stimulation of 1,25(OH)2D production, resulting in excessive urinary phosphate loss. Maintenance of phosphate homeostasis is essential as hyperphosphatemia is a risk factor of cardiovascular calcification, chronic kidney diseases (CKD), and premature aging, while hypophosphatemia is usually associated with rickets and osteomalacia. This chapter elaborates on the possible interactions between vitamin D and phosphate in health and disease.
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