FGF23/Klotho new regulators of vitamin D metabolism

Calcium and phosphorous are coordinately regulated to maintain circulating levels necessary for normal biological functions. Complex hormonal pathways control the levels of calcium and phosphate and prevent adverse consequences of calcium and phosphate excess and deficiencies. At present, at least five hormones have been identified, including 1,25-dihydroxyvitamin D (1,25(OH)₂D), parathyroid hormone (PTH), calcitonin (CT), fibroblast growth factor-23 (FGF23), and Klotho. FGF23 is secreted by osteoblast/osteocytes in bone. 1,25(OH)₂D is produced and secreted from the proximal tubule in the kidney through the respective actions of Cyp27B1 to 1?-hydroxylate 25-hydroxyvitamin D (25(OH)D) to form 1,25(OH)₂D and of Cyp24A1 to 24- hydroxylate 25(OH)D leading to its degradation. The kidney also secretes a soluble form of Klotho, a poorly understood glucosidase and FGFR cofactor that affects calcium, phosphate, and energy homeostasis. The regulation of 1,25(OH)₂D production and degradation by these hormones is a central point for integrating and coordinating the functions of PTH, CT, FGF23, and 1,25(OH)₂D itself. Despite all the recent discoveries, many questions remain unanswered about the regulation and function of FGF23, the integrative physiology of PTH, FGF23, and vitamin D and the pathological significances of these hormones in various disease states. The existence of biological actions of 1,25(OH)₂D and klotho not related to mineral metabolism that include an antiproliferative, prodifferentiating effect on many cell types and immunoregulatory properties, and aging creates a broader role for these factors in health and disease. All such unexplored arenas call for further research.