The metabolic bone disease associated with the Hyp mutation is independent of osteoblastic HIF1α expression

Julia M. Hum, Erica L. Clinkenbeard, Colin Ip, Taryn A. Cass, Matthew Allen, Kenneth White

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Fibroblast growth factor-23 (FGF23) controls key responses to systemic phosphate increases through its phosphaturic actions on the kidney. In addition to stimulation by phosphate, FGF23 positively responds to iron deficiency anemia and hypoxia in rodent models and in humans. The disorder X-linked hypophosphatemia (XLH) is characterized by elevated FGF23 in concert with an intrinsic bone mineralization defect. Indeed, the Hyp mouse XLH model has disturbed osteoblast to osteocyte differentiation with altered expression of a wide variety of genes, including FGF23. The transcription factor Hypoxia inducible factor-1α (HIF1α) has been implicated in regulating FGF23 production and plays a key role in proper bone cell differentiation. Thus the goals of this study were to determine whether HIF1α activation could influence FGF23, and to test osteoblastic HIF1α production on the Hyp endocrine and skeletal phenotypes in vivo. Treatment of primary cultures of osteoblasts/osteocytes and UMR-106 cells with the HIF activator AG490 resulted in rapid HIF1α stabilization and increased Fgf23 mRNA (50–100 fold; p < 0.01–0.001) in a time- and dose-dependent manner. Next, the Phex gene deletion in the Hyp mouse was bred onto mice with a HIF1α/Osteocalcin (OCN)-Cre background. Although HIF1α effects on bone could be detected, FGF23-related phenotypes due to the Hyp mutation were independent of HIF1α in vivo. In summary, FGF23 can be driven by ectopic HIF1α activation under normal iron conditions in vitro, but factors independent of HIF1α activity after mature osteoblast formation are responsible for the disease phenotypes in Hyp mice in vivo.

Original languageEnglish (US)
Pages (from-to)38-43
Number of pages6
JournalBone Reports
Volume6
DOIs
StatePublished - Jun 1 2017

Fingerprint

Hypoxia-Inducible Factor 1
Metabolic Bone Diseases
Mutation
Familial Hypophosphatemic Rickets
Osteoblasts
Osteocytes
Phenotype
Phosphates
Bone and Bones
Physiologic Calcification
Iron-Deficiency Anemias
fibroblast growth factor 23
Osteocalcin
Gene Deletion
Cell Differentiation
Rodentia
Transcription Factors
Iron
Kidney
Messenger RNA

Keywords

  • FGF23
  • Hypoxia inducible factor-1α
  • Phosphate
  • X-linked hypophosphatemia

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

Cite this

The metabolic bone disease associated with the Hyp mutation is independent of osteoblastic HIF1α expression. / Hum, Julia M.; Clinkenbeard, Erica L.; Ip, Colin; Cass, Taryn A.; Allen, Matthew; White, Kenneth.

In: Bone Reports, Vol. 6, 01.06.2017, p. 38-43.

Research output: Contribution to journalArticle

Hum, Julia M. ; Clinkenbeard, Erica L. ; Ip, Colin ; Cass, Taryn A. ; Allen, Matthew ; White, Kenneth. / The metabolic bone disease associated with the Hyp mutation is independent of osteoblastic HIF1α expression. In: Bone Reports. 2017 ; Vol. 6. pp. 38-43.
@article{bcf279e5fd5046ff96bd56496af4592a,
title = "The metabolic bone disease associated with the Hyp mutation is independent of osteoblastic HIF1α expression",
abstract = "Fibroblast growth factor-23 (FGF23) controls key responses to systemic phosphate increases through its phosphaturic actions on the kidney. In addition to stimulation by phosphate, FGF23 positively responds to iron deficiency anemia and hypoxia in rodent models and in humans. The disorder X-linked hypophosphatemia (XLH) is characterized by elevated FGF23 in concert with an intrinsic bone mineralization defect. Indeed, the Hyp mouse XLH model has disturbed osteoblast to osteocyte differentiation with altered expression of a wide variety of genes, including FGF23. The transcription factor Hypoxia inducible factor-1α (HIF1α) has been implicated in regulating FGF23 production and plays a key role in proper bone cell differentiation. Thus the goals of this study were to determine whether HIF1α activation could influence FGF23, and to test osteoblastic HIF1α production on the Hyp endocrine and skeletal phenotypes in vivo. Treatment of primary cultures of osteoblasts/osteocytes and UMR-106 cells with the HIF activator AG490 resulted in rapid HIF1α stabilization and increased Fgf23 mRNA (50–100 fold; p < 0.01–0.001) in a time- and dose-dependent manner. Next, the Phex gene deletion in the Hyp mouse was bred onto mice with a HIF1α/Osteocalcin (OCN)-Cre background. Although HIF1α effects on bone could be detected, FGF23-related phenotypes due to the Hyp mutation were independent of HIF1α in vivo. In summary, FGF23 can be driven by ectopic HIF1α activation under normal iron conditions in vitro, but factors independent of HIF1α activity after mature osteoblast formation are responsible for the disease phenotypes in Hyp mice in vivo.",
keywords = "FGF23, Hypoxia inducible factor-1α, Phosphate, X-linked hypophosphatemia",
author = "Hum, {Julia M.} and Clinkenbeard, {Erica L.} and Colin Ip and Cass, {Taryn A.} and Matthew Allen and Kenneth White",
year = "2017",
month = "6",
day = "1",
doi = "10.1016/j.bonr.2017.01.003",
language = "English (US)",
volume = "6",
pages = "38--43",
journal = "Bone Reports",
issn = "2352-1872",
publisher = "Elsevier Inc.",

}

TY - JOUR

T1 - The metabolic bone disease associated with the Hyp mutation is independent of osteoblastic HIF1α expression

AU - Hum, Julia M.

AU - Clinkenbeard, Erica L.

AU - Ip, Colin

AU - Cass, Taryn A.

AU - Allen, Matthew

AU - White, Kenneth

PY - 2017/6/1

Y1 - 2017/6/1

N2 - Fibroblast growth factor-23 (FGF23) controls key responses to systemic phosphate increases through its phosphaturic actions on the kidney. In addition to stimulation by phosphate, FGF23 positively responds to iron deficiency anemia and hypoxia in rodent models and in humans. The disorder X-linked hypophosphatemia (XLH) is characterized by elevated FGF23 in concert with an intrinsic bone mineralization defect. Indeed, the Hyp mouse XLH model has disturbed osteoblast to osteocyte differentiation with altered expression of a wide variety of genes, including FGF23. The transcription factor Hypoxia inducible factor-1α (HIF1α) has been implicated in regulating FGF23 production and plays a key role in proper bone cell differentiation. Thus the goals of this study were to determine whether HIF1α activation could influence FGF23, and to test osteoblastic HIF1α production on the Hyp endocrine and skeletal phenotypes in vivo. Treatment of primary cultures of osteoblasts/osteocytes and UMR-106 cells with the HIF activator AG490 resulted in rapid HIF1α stabilization and increased Fgf23 mRNA (50–100 fold; p < 0.01–0.001) in a time- and dose-dependent manner. Next, the Phex gene deletion in the Hyp mouse was bred onto mice with a HIF1α/Osteocalcin (OCN)-Cre background. Although HIF1α effects on bone could be detected, FGF23-related phenotypes due to the Hyp mutation were independent of HIF1α in vivo. In summary, FGF23 can be driven by ectopic HIF1α activation under normal iron conditions in vitro, but factors independent of HIF1α activity after mature osteoblast formation are responsible for the disease phenotypes in Hyp mice in vivo.

AB - Fibroblast growth factor-23 (FGF23) controls key responses to systemic phosphate increases through its phosphaturic actions on the kidney. In addition to stimulation by phosphate, FGF23 positively responds to iron deficiency anemia and hypoxia in rodent models and in humans. The disorder X-linked hypophosphatemia (XLH) is characterized by elevated FGF23 in concert with an intrinsic bone mineralization defect. Indeed, the Hyp mouse XLH model has disturbed osteoblast to osteocyte differentiation with altered expression of a wide variety of genes, including FGF23. The transcription factor Hypoxia inducible factor-1α (HIF1α) has been implicated in regulating FGF23 production and plays a key role in proper bone cell differentiation. Thus the goals of this study were to determine whether HIF1α activation could influence FGF23, and to test osteoblastic HIF1α production on the Hyp endocrine and skeletal phenotypes in vivo. Treatment of primary cultures of osteoblasts/osteocytes and UMR-106 cells with the HIF activator AG490 resulted in rapid HIF1α stabilization and increased Fgf23 mRNA (50–100 fold; p < 0.01–0.001) in a time- and dose-dependent manner. Next, the Phex gene deletion in the Hyp mouse was bred onto mice with a HIF1α/Osteocalcin (OCN)-Cre background. Although HIF1α effects on bone could be detected, FGF23-related phenotypes due to the Hyp mutation were independent of HIF1α in vivo. In summary, FGF23 can be driven by ectopic HIF1α activation under normal iron conditions in vitro, but factors independent of HIF1α activity after mature osteoblast formation are responsible for the disease phenotypes in Hyp mice in vivo.

KW - FGF23

KW - Hypoxia inducible factor-1α

KW - Phosphate

KW - X-linked hypophosphatemia

UR - http://www.scopus.com/inward/record.url?scp=85010190197&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85010190197&partnerID=8YFLogxK

U2 - 10.1016/j.bonr.2017.01.003

DO - 10.1016/j.bonr.2017.01.003

M3 - Article

AN - SCOPUS:85010190197

VL - 6

SP - 38

EP - 43

JO - Bone Reports

JF - Bone Reports

SN - 2352-1872

ER -