Conditional Deletion of Murine Fgf23

Interruption of the Normal Skeletal Responses to Phosphate Challenge and Rescue of Genetic Hypophosphatemia

Erica L. Clinkenbeard, Taryn A. Cass, Pu Ni, Julia M. Hum, Teresita Bellido, Matthew Allen, Kenneth White

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

The transgenic and knockout (KO) animals involving Fgf23 have been highly informative in defining novel aspects of mineral metabolism, but are limited by shortened lifespan, inability of spatial/temporal FGF23 control, and infertility of the global KO. To more finely test the role of systemic and genetic influences in FGF23 production, a mouse was developed that carried a floxed ("f")-Fgf23 allele (exon 2 floxed) which demonstrated in vivo recombination when bred to global-Cre transgenic mice (eIIa-cre). Mice homozygous for the recombined allele ("Δ") had undetectable serum intact FGF23, elevated serum phosphate (pΔ/f mice were mated with early osteoblast type Iα1 collagen 2.3-kb promoter-cre mice (Col2.3-cre) and the late osteoblast/early osteocyte Dentin matrix protein-1-cre (Dmp1-cre). Fgf23Δ/f/Col2.3-cre+ and Fgf23Δ/f/Dmp1-cre+ exhibited reduced baseline serum intact FGF23 versus controls. After challenge with high-phosphate diet Cre- mice had 2.1-fold to 2.5-fold increased serum FGF23 (p+ mice had no significant increase, and Dmp1-cre+ mice had only a 37% increase (pΔ/f/Col2.3-cre was bred onto the Hyp (murine X-linked hypophosphatemia [XLH] model) genetic background to test the contribution of osteoblasts and osteocytes to elevated FGF23 and Hyp disease phenotypes. Whereas Hyp mice maintained inappropriately elevated FGF23 considering their marked hypophosphatemia, Hyp/Fgf23Δ/f/Col2.3-cre+ mice had serum FGF23

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Hypophosphatemia
Phosphates
Collagen
Osteoblasts
Osteocytes
Serum
Dentin
Familial Hypophosphatemic Rickets
Alleles
Genetically Modified Animals
Infertility
Transgenic Mice
Genetic Recombination
Minerals
Exons
Proteins

Keywords

  • CRE-RECOMBINASE
  • FGF-23
  • KLOTHO
  • OSTEOBLAST
  • OSTEOCYTE
  • PHOSPHATE
  • VITAMIN D
  • XLH

ASJC Scopus subject areas

  • Orthopedics and Sports Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

@article{37bae024d2be4807b7dc35d4460edf6a,
title = "Conditional Deletion of Murine Fgf23: Interruption of the Normal Skeletal Responses to Phosphate Challenge and Rescue of Genetic Hypophosphatemia",
abstract = "The transgenic and knockout (KO) animals involving Fgf23 have been highly informative in defining novel aspects of mineral metabolism, but are limited by shortened lifespan, inability of spatial/temporal FGF23 control, and infertility of the global KO. To more finely test the role of systemic and genetic influences in FGF23 production, a mouse was developed that carried a floxed ({"}f{"})-Fgf23 allele (exon 2 floxed) which demonstrated in vivo recombination when bred to global-Cre transgenic mice (eIIa-cre). Mice homozygous for the recombined allele ({"}Δ{"}) had undetectable serum intact FGF23, elevated serum phosphate (pΔ/f mice were mated with early osteoblast type Iα1 collagen 2.3-kb promoter-cre mice (Col2.3-cre) and the late osteoblast/early osteocyte Dentin matrix protein-1-cre (Dmp1-cre). Fgf23Δ/f/Col2.3-cre+ and Fgf23Δ/f/Dmp1-cre+ exhibited reduced baseline serum intact FGF23 versus controls. After challenge with high-phosphate diet Cre- mice had 2.1-fold to 2.5-fold increased serum FGF23 (p+ mice had no significant increase, and Dmp1-cre+ mice had only a 37{\%} increase (pΔ/f/Col2.3-cre was bred onto the Hyp (murine X-linked hypophosphatemia [XLH] model) genetic background to test the contribution of osteoblasts and osteocytes to elevated FGF23 and Hyp disease phenotypes. Whereas Hyp mice maintained inappropriately elevated FGF23 considering their marked hypophosphatemia, Hyp/Fgf23Δ/f/Col2.3-cre+ mice had serum FGF23",
keywords = "CRE-RECOMBINASE, FGF-23, KLOTHO, OSTEOBLAST, OSTEOCYTE, PHOSPHATE, VITAMIN D, XLH",
author = "Clinkenbeard, {Erica L.} and Cass, {Taryn A.} and Pu Ni and Hum, {Julia M.} and Teresita Bellido and Matthew Allen and Kenneth White",
year = "2016",
doi = "10.1002/jbmr.2792",
language = "English (US)",
journal = "Journal of Bone and Mineral Research",
issn = "0884-0431",
publisher = "Wiley-Blackwell",

}

TY - JOUR

T1 - Conditional Deletion of Murine Fgf23

T2 - Interruption of the Normal Skeletal Responses to Phosphate Challenge and Rescue of Genetic Hypophosphatemia

AU - Clinkenbeard, Erica L.

AU - Cass, Taryn A.

AU - Ni, Pu

AU - Hum, Julia M.

AU - Bellido, Teresita

AU - Allen, Matthew

AU - White, Kenneth

PY - 2016

Y1 - 2016

N2 - The transgenic and knockout (KO) animals involving Fgf23 have been highly informative in defining novel aspects of mineral metabolism, but are limited by shortened lifespan, inability of spatial/temporal FGF23 control, and infertility of the global KO. To more finely test the role of systemic and genetic influences in FGF23 production, a mouse was developed that carried a floxed ("f")-Fgf23 allele (exon 2 floxed) which demonstrated in vivo recombination when bred to global-Cre transgenic mice (eIIa-cre). Mice homozygous for the recombined allele ("Δ") had undetectable serum intact FGF23, elevated serum phosphate (pΔ/f mice were mated with early osteoblast type Iα1 collagen 2.3-kb promoter-cre mice (Col2.3-cre) and the late osteoblast/early osteocyte Dentin matrix protein-1-cre (Dmp1-cre). Fgf23Δ/f/Col2.3-cre+ and Fgf23Δ/f/Dmp1-cre+ exhibited reduced baseline serum intact FGF23 versus controls. After challenge with high-phosphate diet Cre- mice had 2.1-fold to 2.5-fold increased serum FGF23 (p+ mice had no significant increase, and Dmp1-cre+ mice had only a 37% increase (pΔ/f/Col2.3-cre was bred onto the Hyp (murine X-linked hypophosphatemia [XLH] model) genetic background to test the contribution of osteoblasts and osteocytes to elevated FGF23 and Hyp disease phenotypes. Whereas Hyp mice maintained inappropriately elevated FGF23 considering their marked hypophosphatemia, Hyp/Fgf23Δ/f/Col2.3-cre+ mice had serum FGF23

AB - The transgenic and knockout (KO) animals involving Fgf23 have been highly informative in defining novel aspects of mineral metabolism, but are limited by shortened lifespan, inability of spatial/temporal FGF23 control, and infertility of the global KO. To more finely test the role of systemic and genetic influences in FGF23 production, a mouse was developed that carried a floxed ("f")-Fgf23 allele (exon 2 floxed) which demonstrated in vivo recombination when bred to global-Cre transgenic mice (eIIa-cre). Mice homozygous for the recombined allele ("Δ") had undetectable serum intact FGF23, elevated serum phosphate (pΔ/f mice were mated with early osteoblast type Iα1 collagen 2.3-kb promoter-cre mice (Col2.3-cre) and the late osteoblast/early osteocyte Dentin matrix protein-1-cre (Dmp1-cre). Fgf23Δ/f/Col2.3-cre+ and Fgf23Δ/f/Dmp1-cre+ exhibited reduced baseline serum intact FGF23 versus controls. After challenge with high-phosphate diet Cre- mice had 2.1-fold to 2.5-fold increased serum FGF23 (p+ mice had no significant increase, and Dmp1-cre+ mice had only a 37% increase (pΔ/f/Col2.3-cre was bred onto the Hyp (murine X-linked hypophosphatemia [XLH] model) genetic background to test the contribution of osteoblasts and osteocytes to elevated FGF23 and Hyp disease phenotypes. Whereas Hyp mice maintained inappropriately elevated FGF23 considering their marked hypophosphatemia, Hyp/Fgf23Δ/f/Col2.3-cre+ mice had serum FGF23

KW - CRE-RECOMBINASE

KW - FGF-23

KW - KLOTHO

KW - OSTEOBLAST

KW - OSTEOCYTE

KW - PHOSPHATE

KW - VITAMIN D

KW - XLH

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U2 - 10.1002/jbmr.2792

DO - 10.1002/jbmr.2792

M3 - Article

JO - Journal of Bone and Mineral Research

JF - Journal of Bone and Mineral Research

SN - 0884-0431

ER -