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Transgenic Mice Overexpressing Human Fibroblast Growth Factor 23 (R176Q) Delineate a Putative Role for Parathyroid Hormone in Renal Phosphate Wasting Disorders
Abstract
Fibroblast growth factor 23 (FGF23) is a recently characterized protein likely involved in the regulation of serum phosphate homeostasis. Increased circulating levels of FGF23 have been reported in patients with renal phosphate-wasting disorders, but it is unclear whether FGF23 is the direct mediator responsible for the decreased phosphate transport at the proximal renal tubules and the altered vitamin D metabolism associated with these states. To examine this question, we generated transgenic mice expressing and secreting from the liver human FGF23 (R176Q), a mutant form that fails to be degraded by furin proteases. At 1 and 2 months of age, mice carrying the transgene recapitulated the biochemical (decreased urinary phosphate reabsorption, hypophosphatemia, low serum 1,25-dihydroxyvitamin D3) and skeletal (rickets and osteomalacia) alterations associated with these disorders. Unexpectantly, marked changes in parameters of calcium homeostasis were also observed, consistent with secondary hyperparathyroidism. Moreover, in the kidney the anticipated alterations in the expression of hydroxylases associated with vitamin D metabolism were not observed despite the profound hypophosphatemia and increased circulating levels of PTH, both major physiological stimuli for 1,25-dihydroxyvitamin D3 production. Our findings strongly support the novel concept that high circulating levels of FGF23 are associated with profound disturbances in the regulation of phosphate and vitamin D metabolism as well as calcium homeostasis and that elevated PTH levels likely also contribute to the renal phosphate wasting associated with these disorders.
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“suggesting that in the current study elevated iFGF23 did not inhibit PTH secretion but rather PTH stimulated iFGF23, eventually to lower plasma Pi [4, 39].”
From Controlled dietary phosphate loading in healthy young men elevates plasma phosphate and FGF23 levels (2025) · cites this paper as [4]
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Metadata
- Authors
- Bai, X., Miao, D., Li, J., Goltzman, D., & Karaplis, A. C.
- Affiliations
- Jewish General Hospital (CA)
- McGill University Health Centre (CA)
- Corresponding author
- Karaplis, Andrew C.
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2004-11-01
- Volume
- 145
- Issue
- 11
- Pages
- 5269-5279
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- OpenAlex
- W2144414222
- Cited by
- 329
- References
- 55
- Citations by year
- 2026: 6 · 2025: 2 · 2024: 3 · 2023: 7 · 2022: 9 · 2021: 7 · 2020: 9 · 2019: 11 · 2018: 17 · 2017: 12 · 2016: 25 · 2015: 11 · 2014: 11 · 2013: 13 · 2012: 33
- FWCI
- 13.11
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- Canadian Institutes of Health Research
- National Cancer Institute
- Canadian Arthritis Network
- Topics
- Health Sciences › Medicine › Nephrology › Parathyroid Disorders and Treatments
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Alkaline Phosphatase Research Studies
- Health Sciences › Medicine › Nephrology › Renal function and acid-base balance
- Keywords
- fibroblast growth factor 23, parathyroid hormone, renal phosphate wasting, hypophosphatemia, vitamin D metabolism, 1,25-dihydroxyvitamin D3, secondary hyperparathyroidism, calcium homeostasis, osteomalacia, rickets, transgenic mice, furin protease
- MeSH terms
- Fibroblast Growth Factor-23, Animals, Bone and Bones, Calcium, Female, Fibroblast Growth Factors, Carcinoma, Hepatocellular, Humans, Hypophosphatemia, Familial, Kidney Tubules, Proximal, Male, Mice, Transgenic, Osteomalacia, Parathyroid Hormone, Phosphates, Pregnancy, Vitamin D, Gene Expression, Cell Line, Tumor, Mice
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