The pathophysiological mechanisms that underlie metabolic bone diseases due to impaired phosphate homeostasis are incompletely understood. Investigating the molecular etiology of disorders caused by disturbed mineral metabolism has been instrumental in identifying new circulating regulators of phosphate homeostasis, collectively referred to as `phosphatonins.'We identified the phosphatonin Fibroblast growth factor-23 (FGF23) in a positional cloning approach to isolate the gene for autosomal dominant hypophosphatemic rickets (ADHR), characterized by hypophosphatemia secondary to renal phosphate wasting, rickets/osteomalacia and fracture. Building upon this work during the current grant cycle, our group discovered the molecular basis for a novel recessive phosphate wasting disorder associated with elevated FGF23, as well as determined that the mirror-image disorder to ADHR, familial tumoral calcinosis (TC), is caused by recessive FGF23 loss of function mutations. A TC phenotype is also present in the Klotho (KL)-null mouse, and our data demonstrate that FGF23 elicits its biological actions through this receptor-like molecule. However, the KL isoform that mediates FGF23-dependent bioactivity is unknown. Our preliminary findings using a novel knock in mouse carrying a human ADHR Fgf23 mutation demonstrate the presence of unique skeletal alterations, providing new insight into FGF23 function in vivo. Although significant progress has been made determining the roles of FGF23 in normal circumstances and in disease, the mechanisms whereby FGF23 controls phosphate handling remain unclear. Thus, the central hypothesis to be tested within this proposal is: FGF23 is secreted from bone cells in a regulated manner and acts through specific target molecules to control phosphate homeostasis in the kidney. We will address this hypothesis by undertaking the following specific aims: To test the molecular mechanisms underlying ADHR using a murine knock in model;to determine the role of KL in the renal proximal tubule and distal tubule actions of FGF23;and to test the KL isoforms for the ability to direct FGF23 bioactivity in vivo. These investigations will, over the long term, provide critical insight into the pathogenesis of syndromes associated with altered FGF23 expression, into more common disorders of disturbed phosphate homeostasis, as well as into the basic biology of phosphate homeostasis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK063934-09
Application #
8016670
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Kimmel, Paul
Project Start
2002-12-27
Project End
2012-03-31
Budget Start
2010-12-01
Budget End
2012-03-31
Support Year
9
Fiscal Year
2011
Total Cost
$314,489
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Genetics
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Hum, Julia M; Clinkenbeard, Erica L; Ip, Colin et al. (2017) The metabolic bone disease associated with the Hyp mutation is independent of osteoblastic HIF1? expression. Bone Rep 6:38-43
Hum, Julia M; O'Bryan, Linda; Smith, Rosamund C et al. (2017) Novel functions of circulating Klotho. Bone 100:36-40
Clinkenbeard, Erica L; White, Kenneth E (2017) Heritable and acquired disorders of phosphate metabolism: Etiologies involving FGF23 and current therapeutics. Bone 102:31-39
Hum, Julia M; O'Bryan, Linda M; Tatiparthi, Arun K et al. (2017) Chronic Hyperphosphatemia and Vascular Calcification Are Reduced by Stable Delivery of Soluble Klotho. J Am Soc Nephrol 28:1162-1174
Knab, Vanessa M; Corbin, Braden; Andrukhova, Olena et al. (2017) Acute Parathyroid Hormone Injection Increases C-Terminal but Not Intact Fibroblast Growth Factor 23 Levels. Endocrinology 158:1130-1139
Clinkenbeard, Erica L; Hanudel, Mark R; Stayrook, Keith R et al. (2017) Erythropoietin stimulates murine and human fibroblast growth factor-23, revealing novel roles for bone and bone marrow. Haematologica 102:e427-e430
Fleet, James C; Replogle, Rebecca A; Reyes-Fernandez, Perla et al. (2016) Gene-by-Diet Interactions Affect Serum 1,25-Dihydroxyvitamin D Levels in Male BXD Recombinant Inbred Mice. Endocrinology 157:470-81
Clinkenbeard, Erica L; Cass, Taryn A; Ni, Pu et al. (2016) Conditional Deletion of Murine Fgf23: Interruption of the Normal Skeletal Responses to Phosphate Challenge and Rescue of Genetic Hypophosphatemia. J Bone Miner Res 31:1247-57
Murali, Sathish K; Andrukhova, Olena; Clinkenbeard, Erica L et al. (2016) Excessive Osteocytic Fgf23 Secretion Contributes to Pyrophosphate Accumulation and Mineralization Defect in Hyp Mice. PLoS Biol 14:e1002427
Clinkenbeard, Erica L; White, Kenneth E (2016) Systemic Control of Bone Homeostasis by FGF23 Signaling. Curr Mol Biol Rep 2:62-71

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