There is evidence for a hormone/enzyme/extracellular matrix protein cascade for maintaining systemic phosphate homeostasis and mineralization. Genetic studies of Autosomal Dominant Hypophosphatemic Rickets (ADHR) and X-linked hypophosphatemia (XLH) identified the phosphaturic hormone FGF23 and the membrane metalloprotease PHEX, while investigations of Tumor Induced Osteomalacia (TIO) discovered the extracellular matrix protein MEPE. Similarities between ADHR, XLH, and TIO provide the basis for a compelling model to explain the common pathogenesis of renal phosphate wasting and defective mineralization in these disorders. In this model, circulating phosphaturic hormone, FGF23, and local inhibitor(s) of mineralization, MEPE, respectively cause renal phosphate wasting and intrinsic mineralization abnormalities. We have data that XLH is caused by inactivating mutations of Phex that leads to altered activity of unidentified oligopeptide substrates that secondarily modify the expression and/or degradation of the phosphaturic factor FGF23 and the mineralization inhibitor MEPE.
In Aim 1 we will use mouse genetic approaches to establish a cause-and-effect relationship between increased FGF23 and hypophosphatemia in Phex-deficient Hyp mouse homologue of XLH. In these studies, Phex-deficient Hyp mice will be transferred onto FGF23 null background to attempt rescue of the Hyp phenotype. We will also explore the molecular mechanisms whereby FGF23 regulates renal phosphate handling and skeletal mineralization by examining the effects of FGF23 administration in mice lacking specific fibroblastic growth factor receptors.
In Aim 2, we will investigate the role that MEPE plays in the apparent intrinsic mineralization defect by transferring Phex-deficiency onto the MEPE null background. Finally, in Aim 3 we will use complementary phage display and yeast-two hybrid screening to identify physiologically relevant Phex substrates, inhibitors and/or interacting proteins that allow this enzyme to control FGF23 and MEPE metabolism.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR045955-10
Application #
7238699
Study Section
Orthopedics and Musculoskeletal Study Section (ORTH)
Program Officer
Sharrock, William J
Project Start
1999-04-05
Project End
2009-05-31
Budget Start
2007-06-01
Budget End
2008-05-31
Support Year
10
Fiscal Year
2007
Total Cost
$306,642
Indirect Cost
Name
University of Kansas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
016060860
City
Kansas City
State
KS
Country
United States
Zip Code
66160
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