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
Fitzpatrick, Elizabeth A; Han, Xiaobin; Xiao, Zhousheng et al. (2018) Role of Fibroblast Growth Factor-23 in Innate Immune Responses. Front Endocrinol (Lausanne) 9:320
Kovesdy, Csaba P; Lu, Jun Ling; Wall, Barry M et al. (2018) Changes With Lanthanum Carbonate, Calcium Acetate, and Phosphorus Restriction in CKD: A Randomized Controlled Trial. Kidney Int Rep 3:897-904
Pi, Min; Ye, Ruisong; Han, Xiaobin et al. (2018) Cardiovascular Interactions between Fibroblast Growth Factor-23 and Angiotensin II. Sci Rep 8:12398
Han, Xiaobin; Quarles, L Darryl (2018) Letter to the Editor: ""Increased Circulating FGF23 Does Not Lead to Cardiac Hypertrophy in the Male Hyp Mouse Model of XLH"". Endocrinology 159:3655-3656
Han, Xiaobin; Ross, Jed; Kolumam, Ganesh et al. (2018) Cardiovascular Effects of Renal Distal Tubule Deletion of the FGF Receptor 1 Gene. J Am Soc Nephrol 29:69-80
Xiao, Zhousheng; Baudry, Jerome; Cao, Li et al. (2018) Polycystin-1 interacts with TAZ to stimulate osteoblastogenesis and inhibit adipogenesis. J Clin Invest 128:157-174
Han, Xiaobin; Li, Linqiang; Yang, Jiancheng et al. (2016) Counter-regulatory paracrine actions of FGF-23 and 1,25(OH)2 D in macrophages. FEBS Lett 590:53-67
Han, Xiaobin; Quarles, L Darryl (2016) Multiple faces of fibroblast growth factor-23. Curr Opin Nephrol Hypertens 25:333-42
Han, Xiaobin; Yang, Jiancheng; Li, Linqiang et al. (2016) Conditional Deletion of Fgfr1 in the Proximal and Distal Tubule Identifies Distinct Roles in Phosphate and Calcium Transport. PLoS One 11:e0147845
Zhang, Qian; Doucet, Michele; Tomlinson, Ryan E et al. (2016) The hypoxia-inducible factor-1? activates ectopic production of fibroblast growth factor 23 in tumor-induced osteomalacia. Bone Res 4:16011

Showing the most recent 10 out of 63 publications