ArticleJournal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research2012
A Phex mutation in a murine model of X-linked hypophosphatemia alters phosphate responsiveness of bone cells.
Article in Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 37 citations in OpenAlex.
- Fibroblast growth factor 23: Regulation, signalling and systemic links between bone, metabolism and inflammation.Molecular metabolism · 2026Review
- The contribution of a novelFrontiers in endocrinology · 2023Article
- X-Linked Hypophosphatemia: A New Era in Management.Journal of the Endocrine Society · 2020Review
- New Developments in the Treatment of X-Linked Hypophosphataemia: Implications for Clinical Management.Paediatric drugs · 2020Review
- FGF23 and its role in X-linked hypophosphatemia-related morbidity.Orphanet journal of rare diseases · 2019Review
- Physiological Actions of Fibroblast Growth Factor-23.Frontiers in endocrinology · 2018Review
- Genetic Knockout and Rescue Studies in Mice Unravel Abnormal Phosphorus Threshold in Hypophosphatemic Rickets.Endocrinology · 2017Article
- A Mutation in the Dmp1 Gene Alters Phosphate Responsiveness in Mice.Endocrinology · 2017Article
- Article
- Conditional Deletion of Murine Fgf23: Interruption of the Normal Skeletal Responses to Phosphate Challenge and Rescue of Genetic Hypophosphatemia.Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research · 2016Article
- Excessive Osteocytic Fgf23 Secretion Contributes to Pyrophosphate Accumulation and Mineralization Defect in Hyp Mice.PLoS biology · 2016Article
- Hyperphosphatemic familial tumoral calcinosis: genetic models of deficient FGF23 action.Current osteoporosis reports · 2015Review
- Genetic rescue of glycosylation-deficient Fgf23 in the Galnt3 knockout mouse.Endocrinology · 2014Article
- Regulation of serum phosphate.The Journal of physiology · 2014Review
- Hypophosphatemic rickets: revealing novel control points for phosphate homeostasis.Current osteoporosis reports · 2014Review
- Article
- Osteocyte-specific deletion of Fgfr1 suppresses FGF23.PloS one · 2014Article
- Dosage effect of a Phex mutation in a murine model of X-linked hypophosphatemia.Calcified tissue international · 2013Article
- Fibrous dysplasia and fibroblast growth factor-23 regulation.Current osteoporosis reports · 2013Review
- The changing face of hypophosphatemic disorders in the FGF-23 era.Pediatric endocrinology reviews : PER · 2013Review
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
Mutations in the PHEX gene cause X-linked hypophosphatemia (XLH). Hypophosphatemia in XLH results from increased circulating levels of a phosphaturic hormone, fibroblast growth factor 23 (FGF23), which inhibits renal phosphate reabsorption and 1,25-dihydroxyvitamin D (calcitriol) synthesis. The current standard therapy for XLH--high-dose phosphate and calcitriol--further increases FGF23 concentrations, suggesting that patients with XLH may have an altered response to extracellular phosphate. To test for the presence of abnormal phosphate responsiveness, we compared serum biochemistries and femoral Fgf23 mRNA expression between wild-type mice, murine models of XLH (Phex(K496X)) and hyperphosphatemic tumoral calcinosis (Galnt3(-/-)), and Galnt3/Phex double-mutant mice. Phex mutant mice had not only increased Fgf23 expression but also reduced proteolytic cleavage of intact Fgf23 protein, resulting in markedly elevated intact Fgf23 levels and consequent hypophosphatemia. In contrast, despite markedly increased Fgf23 expression, Galnt3 knockout mice had significantly high proteolytic cleavage of Fgf23 protein, leading to low intact Fgf23 concentrations and hyperphosphatemia. Galnt3/Phex double-mutant mice had an intermediate biochemical phenotype between wild-type and Phex mutant mice, including slightly elevated intact Fgf23 concentrations with milder hypophosphatemia. Despite the hypophosphatemia, double-mutant mice attempted to reduce serum phosphate back to the level of Phex mutant mice by upregulating Fgf23 expression as much as 24-fold higher than Phex mutant mice. These data suggest that Phex mutations alter the responsiveness of bone cells to extracellular phosphate concentrations and may create a lower set point for "normal" phosphate levels.
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