? Phosphate (PO4) is essential for bone mineralization, muscle function, signal transduction and the creation and utilization of energy. Abnormal PO4 handling occurs in forms of hypophosphatemic rickets, and in chronic renal failure with resultant parathyroid hyperplasia and osteodystrophy. Data from three PO4 wasting disorders (X-linked hypophosphatemia, autosomal dominant hypophosphatemic rickets, and tumor induced osteomalacia) demonstrate that fibroblast growth factor 23 (FGF-23) is a novel phosphaturic hormone that is responsible for severe phosphate wasting in these rare patients. The overarching goal of this proposal is to describe the role of FGF-23 in normal P04 physiology and factors that regulate FGF-23. In each of these protocols, we will measure FGF-23, blood and urinary PO4, and other hormones known to affect PO4, like parathyroid hormone (PTH) and 1,25 dihydroxyvitamin D.
In Specific Aim 1, 20 healthy subjects will consume a research diet, and undergo 24 hour blood and urine frequent sampling to assess the diurnal variation in FGF-23. We hypothesize that the diurnal variation in FGF-23, as measured by cosinor analysis, will parallel that of blood PO4 and the renal clearance of PO4, and differ from that of PTH.
In Specific Aim 2, 100 healthy vitamin D-deficient subjects will be randomly assigned to calcium 500 mg BID or calcium 500 mg BID plus vitamin D 50,000 units Q WK for 12 weeks to determine whether vitamin D increases FGF-23 levels after controlling for changes in blood PO4 and PTH. To determine the effects of PTH suppression on FGF-23, in Specific Aim 3, 44 healthy subjects will be randomly assigned to either placebo or a calcimimetic, Cinacalcet 30 mg QD (which lowers PTH levels), and concurrently phosphate loaded to determine whether P04 loading increases FGF-23 levels independently of PTH. Finally, to determine effect of PTH stimulation on FGF-23, in Specific Aim 4, we will measure FGF-23 in 58 healthy men who were infused with human PTH(1-34) at a dose of 0.55 U/kg/hr to determine whether PTH has a direct effect on FGF-23 in humans. To summarize, FGF-23 is responsible for phosphate wasting in several rare disorders and appears to play a vital role in normal phosphate physiology. The studies in this proposal will advance our understanding of the hormonal regulation of FGF-23 in humans and may help in the development of novel treatments for patients with hypo- or hyperphosphatemic disorders. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
1K23DK073356-01A1
Application #
7147855
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Podskalny, Judith M,
Project Start
2006-08-01
Project End
2011-06-30
Budget Start
2006-08-01
Budget End
2007-06-30
Support Year
1
Fiscal Year
2006
Total Cost
$145,546
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Mitchell, Deborah M; Jüppner, Harald; Burnett-Bowie, Sherri-Ann M (2017) FGF23 Is Not Associated With Age-Related Changes in Phosphate, but Enhances Renal Calcium Reabsorption in Girls. J Clin Endocrinol Metab 102:1151-1160
Burnett-Bowie, Sherri-Ann M; Leder, Benjamin Z; Henao, Maria P et al. (2012) Randomized trial assessing the effects of ergocalciferol administration on circulating FGF23. Clin J Am Soc Nephrol 7:624-31
Mitchell, Deborah M; Henao, Maria P; Finkelstein, Joel S et al. (2012) Prevalence and predictors of vitamin D deficiency in healthy adults. Endocr Pract 18:914-23
Bell, Taison D; Demay, Marie B; Burnett-Bowie, Sherri-Ann M (2010) The biology and pathology of vitamin D control in bone. J Cell Biochem 111:7-13
Burnett-Bowie, Sherri-Ann M; Henao, Maria P; Dere, Melissa E et al. (2009) Effects of hPTH(1-34) infusion on circulating serum phosphate, 1,25-dihydroxyvitamin D, and FGF23 levels in healthy men. J Bone Miner Res 24:1681-5