Longitudinal evaluation of FGF23 changes and mineral metabolism abnormalities in a mouse model of chronic kidney disease

Jason R. Stubbs, Nan He, Arun Idiculla, Ryan Gillihan, Shiguang Liu, Valentin David, Yan Hong, Leigh Quarles

Research output: Contribution to journalArticle

55 Citations (Scopus)

Abstract

Fibroblast growth factor 23 (FGF23) is a phosphaturic and vitamin D-regulatory hormone of putative bone origin that is elevated in patients with chronic kidney disease (CKD). The mechanisms responsible for elevations of FGF23 and its role in the pathogenesis of chronic kidney disease-mineral bone disorder (CKD-MBD) remain uncertain. We investigated the association between FGF23 serum levels and kidney disease progression, as well as the phenotypic features of CKD-MBD in a Col4a3 null mouse model of human autosomal-recessive Alport syndrome. These mice exhibited progressive renal failure, declining 1,25(OH)2D levels, increments in parathyroid hormone (PTH) and FGF23, late-onset hypocalcemia and hyperphosphatemia, high-turnover bone disease, and increased mortality. Serum levels of FGF23 increased in the earliest stages of renal damage, before elevations in blood urea nitrogen (BUN) and creatinine. FGF23 gene transcription in bone, however, did not increase until late-stage kidney disease, when serum FGF23 levels were exponentially elevated. Further evaluation of bone revealed trabecular osteocytes to be the primary cell source for FGF23 production in late-stage disease. Changes in FGF23 mirrored the rise in serum PTH and the decline in circulating 1,25(OH)2D. The rise in PTH and FGF23 in Col4a3 null mice coincided with an increase in the urinary fractional excretion of phosphorus and a progressive decline in sodium-phosphate cotransporter gene expression in the kidney. Our findings suggest elevations of FGF23 in CKD to be an early marker of renal injury that increases before BUN and serum creatinine. An increased production of FGF23 by bone may not be responsible for early increments in FGF23 in CKD but does appear to contribute to FGF23 levels in late-stage disease. Elevations in FGF23 and PTH coincide with an increase in urinary phosphate excretion that likely prevents the early onset of hyperphosphatemia in the face of increased bone turnover and a progressive decline in functional renal mass.

Original languageEnglish (US)
Pages (from-to)38-46
Number of pages9
JournalJournal of Bone and Mineral Research
Volume27
Issue number1
DOIs
StatePublished - Jan 1 2012

Fingerprint

Chronic Renal Insufficiency
Minerals
Parathyroid Hormone
Hyperphosphatemia
Kidney
Serum
Blood Urea Nitrogen
fibroblast growth factor 23
Kidney Diseases
Bone and Bones
Creatinine
Sodium-Phosphate Cotransporter Proteins
Hereditary Nephritis
Chronic Kidney Disease-Mineral and Bone Disorder
Osteocytes
Hypocalcemia
Bone Remodeling
Bone Diseases
Vitamin D
Phosphorus

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

Cite this

Longitudinal evaluation of FGF23 changes and mineral metabolism abnormalities in a mouse model of chronic kidney disease. / Stubbs, Jason R.; He, Nan; Idiculla, Arun; Gillihan, Ryan; Liu, Shiguang; David, Valentin; Hong, Yan; Quarles, Leigh.

In: Journal of Bone and Mineral Research, Vol. 27, No. 1, 01.01.2012, p. 38-46.

Research output: Contribution to journalArticle

Stubbs, Jason R. ; He, Nan ; Idiculla, Arun ; Gillihan, Ryan ; Liu, Shiguang ; David, Valentin ; Hong, Yan ; Quarles, Leigh. / Longitudinal evaluation of FGF23 changes and mineral metabolism abnormalities in a mouse model of chronic kidney disease. In: Journal of Bone and Mineral Research. 2012 ; Vol. 27, No. 1. pp. 38-46.
@article{3402b03380584fc2b142f0ab53f9f667,
title = "Longitudinal evaluation of FGF23 changes and mineral metabolism abnormalities in a mouse model of chronic kidney disease",
abstract = "Fibroblast growth factor 23 (FGF23) is a phosphaturic and vitamin D-regulatory hormone of putative bone origin that is elevated in patients with chronic kidney disease (CKD). The mechanisms responsible for elevations of FGF23 and its role in the pathogenesis of chronic kidney disease-mineral bone disorder (CKD-MBD) remain uncertain. We investigated the association between FGF23 serum levels and kidney disease progression, as well as the phenotypic features of CKD-MBD in a Col4a3 null mouse model of human autosomal-recessive Alport syndrome. These mice exhibited progressive renal failure, declining 1,25(OH)2D levels, increments in parathyroid hormone (PTH) and FGF23, late-onset hypocalcemia and hyperphosphatemia, high-turnover bone disease, and increased mortality. Serum levels of FGF23 increased in the earliest stages of renal damage, before elevations in blood urea nitrogen (BUN) and creatinine. FGF23 gene transcription in bone, however, did not increase until late-stage kidney disease, when serum FGF23 levels were exponentially elevated. Further evaluation of bone revealed trabecular osteocytes to be the primary cell source for FGF23 production in late-stage disease. Changes in FGF23 mirrored the rise in serum PTH and the decline in circulating 1,25(OH)2D. The rise in PTH and FGF23 in Col4a3 null mice coincided with an increase in the urinary fractional excretion of phosphorus and a progressive decline in sodium-phosphate cotransporter gene expression in the kidney. Our findings suggest elevations of FGF23 in CKD to be an early marker of renal injury that increases before BUN and serum creatinine. An increased production of FGF23 by bone may not be responsible for early increments in FGF23 in CKD but does appear to contribute to FGF23 levels in late-stage disease. Elevations in FGF23 and PTH coincide with an increase in urinary phosphate excretion that likely prevents the early onset of hyperphosphatemia in the face of increased bone turnover and a progressive decline in functional renal mass.",
author = "Stubbs, {Jason R.} and Nan He and Arun Idiculla and Ryan Gillihan and Shiguang Liu and Valentin David and Yan Hong and Leigh Quarles",
year = "2012",
month = "1",
day = "1",
doi = "10.1002/jbmr.516",
language = "English (US)",
volume = "27",
pages = "38--46",
journal = "Journal of Bone and Mineral Research",
issn = "0884-0431",
publisher = "Wiley-Blackwell",
number = "1",

}

TY - JOUR

T1 - Longitudinal evaluation of FGF23 changes and mineral metabolism abnormalities in a mouse model of chronic kidney disease

AU - Stubbs, Jason R.

AU - He, Nan

AU - Idiculla, Arun

AU - Gillihan, Ryan

AU - Liu, Shiguang

AU - David, Valentin

AU - Hong, Yan

AU - Quarles, Leigh

PY - 2012/1/1

Y1 - 2012/1/1

N2 - Fibroblast growth factor 23 (FGF23) is a phosphaturic and vitamin D-regulatory hormone of putative bone origin that is elevated in patients with chronic kidney disease (CKD). The mechanisms responsible for elevations of FGF23 and its role in the pathogenesis of chronic kidney disease-mineral bone disorder (CKD-MBD) remain uncertain. We investigated the association between FGF23 serum levels and kidney disease progression, as well as the phenotypic features of CKD-MBD in a Col4a3 null mouse model of human autosomal-recessive Alport syndrome. These mice exhibited progressive renal failure, declining 1,25(OH)2D levels, increments in parathyroid hormone (PTH) and FGF23, late-onset hypocalcemia and hyperphosphatemia, high-turnover bone disease, and increased mortality. Serum levels of FGF23 increased in the earliest stages of renal damage, before elevations in blood urea nitrogen (BUN) and creatinine. FGF23 gene transcription in bone, however, did not increase until late-stage kidney disease, when serum FGF23 levels were exponentially elevated. Further evaluation of bone revealed trabecular osteocytes to be the primary cell source for FGF23 production in late-stage disease. Changes in FGF23 mirrored the rise in serum PTH and the decline in circulating 1,25(OH)2D. The rise in PTH and FGF23 in Col4a3 null mice coincided with an increase in the urinary fractional excretion of phosphorus and a progressive decline in sodium-phosphate cotransporter gene expression in the kidney. Our findings suggest elevations of FGF23 in CKD to be an early marker of renal injury that increases before BUN and serum creatinine. An increased production of FGF23 by bone may not be responsible for early increments in FGF23 in CKD but does appear to contribute to FGF23 levels in late-stage disease. Elevations in FGF23 and PTH coincide with an increase in urinary phosphate excretion that likely prevents the early onset of hyperphosphatemia in the face of increased bone turnover and a progressive decline in functional renal mass.

AB - Fibroblast growth factor 23 (FGF23) is a phosphaturic and vitamin D-regulatory hormone of putative bone origin that is elevated in patients with chronic kidney disease (CKD). The mechanisms responsible for elevations of FGF23 and its role in the pathogenesis of chronic kidney disease-mineral bone disorder (CKD-MBD) remain uncertain. We investigated the association between FGF23 serum levels and kidney disease progression, as well as the phenotypic features of CKD-MBD in a Col4a3 null mouse model of human autosomal-recessive Alport syndrome. These mice exhibited progressive renal failure, declining 1,25(OH)2D levels, increments in parathyroid hormone (PTH) and FGF23, late-onset hypocalcemia and hyperphosphatemia, high-turnover bone disease, and increased mortality. Serum levels of FGF23 increased in the earliest stages of renal damage, before elevations in blood urea nitrogen (BUN) and creatinine. FGF23 gene transcription in bone, however, did not increase until late-stage kidney disease, when serum FGF23 levels were exponentially elevated. Further evaluation of bone revealed trabecular osteocytes to be the primary cell source for FGF23 production in late-stage disease. Changes in FGF23 mirrored the rise in serum PTH and the decline in circulating 1,25(OH)2D. The rise in PTH and FGF23 in Col4a3 null mice coincided with an increase in the urinary fractional excretion of phosphorus and a progressive decline in sodium-phosphate cotransporter gene expression in the kidney. Our findings suggest elevations of FGF23 in CKD to be an early marker of renal injury that increases before BUN and serum creatinine. An increased production of FGF23 by bone may not be responsible for early increments in FGF23 in CKD but does appear to contribute to FGF23 levels in late-stage disease. Elevations in FGF23 and PTH coincide with an increase in urinary phosphate excretion that likely prevents the early onset of hyperphosphatemia in the face of increased bone turnover and a progressive decline in functional renal mass.

UR - http://www.scopus.com/inward/record.url?scp=84555187565&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84555187565&partnerID=8YFLogxK

U2 - 10.1002/jbmr.516

DO - 10.1002/jbmr.516

M3 - Article

C2 - 22031097

AN - SCOPUS:84555187565

VL - 27

SP - 38

EP - 46

JO - Journal of Bone and Mineral Research

JF - Journal of Bone and Mineral Research

SN - 0884-0431

IS - 1

ER -