Physiologic Regulation of FGF-23

Vitamin D and phosphate are central to normal mineral homeostasis and important in many physiologic functions including skeletal integrity. For several decades parathyroid hormone (PTH) has been recognized as a central regulator of serum vitamin D and phosphate levels. Recently, FGF-23 has been identified as central in the regulation of the metabolism of vitamin D and serum phosphorus. The organ primarily responsible for the physiologic production of FGF-23 appears to be the skeleton. The study of FGF-23 metabolism and its direct effect on mineral metabolism is confounded by the classic endocrine feedback loops that exist among serum calcium, phosphorus, 1,25-(OH)2-vitamin D (1,25-D), and PTH. It is possible that any of these (phosphorus, calcium, 1,25-D, and/or PTH) are important in the regulation of serum FGF-23. The goal of this study is to identify what factors regulate serum FGF-23. To overcome the confounding effect of PTH, we will study patients deficient in PTH (hypoparathyroidism) or resistant to PTH at the kidney (pseudohypoparathyroidism type 1B, PHP1B). The kidney is one of the primary organs responsible for regulating serum phosphorus and generating 1,25-D. It is the target of PTH and FGF-23. While patients with PHP1B are resistant to the action of PTH at the kidney, they are sensitive to the action of PTH at the bone, the tissue that produces FGF-23. Physiologic manipulation of the serum phosphorus, 1,25-D, calcium, and PTH in subjects with hypoparathyroidism or PHP1B will allow for a nearly complete dissection of the factors that are potential regulators of serum FGF-23.