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Abstract: TH-OR12

Hypoxia-Inducible Factor 1 Alpha Regulates FGF-23 Production and Bone Metabolism in CKD

Session Information

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic

Authors

  • Courbon, Guillaume, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Martinez-Calle, Marta, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Spindler, Jadeah Jeannine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Hunt-Tobey, Bridget, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Lynch, Emily Patricia, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Wang, Xueyan, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Martin, Aline, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • David, Valentin, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
Background

Renal osteodystrophy (ROD) is a complex bone disorder associated with chronic kidney disease (CKD) which affects over one in ten Americans. CKD also leads to increased bone production of the phosphate regulating hormone, fibroblast growth factor 23 (FGF23). ROD and FGF23 are associated with adverse clinical outcomes, including cardiovascular events and death. Hypoxia-inducible factor 1 alpha (HIF1α) regulates FGF23 expression in osteoblasts and osteocytes, and we hypothesized that osseous HIF1α plays an important role in ROD and FGF23 excess in CKD.

Methods

We generated mice harboring a conditional deletion of Hif1α in osteocytes (Hif1αDmp1-cKO) and crossed them to Col4a3KO mice, a mouse model of progressive CKD. We studied bone and mineral metabolism alterations of wild-type (WT), Hif1αDmp1-cKO, Col4a3KO and compound Col4a3KO Hif1αDmp1-cKO (CPD) mice. In parallel, we also treated 6 week-old WT and Col4a3KO mice with a HIF inhibitor (BAY 87-2243) for 4 weeks. Finally, we compared the differentiation and mineralization potential of newly generated MC3T3-E1 osteoblast cell lines overexpressing Hif1α (Hif1αTg) or Hif1α shRNA (Hif1αKO) to MC3T3-E1 transfected with an empty vector (Ctr).

Results

Deletion of Hif1α delayed progression of CKD, as CPD mice showed reduced levels of BUN compared to age-matched Col4a3KO mice (-25%). CPD mice also showed lower FGF23 levels (-80% vs. Col4a3KO) and we obtained similar results in Col4a3KO mice administered with a HIF inhibitor (-80% FGF23, -30% BUN, vs. Ctr-Col4a3KO). CPD mice also showed improved trabecular and cortical bone parameters (+50% trabecular bone volume, -20% cortical porosity vs. Col4a3KO). Finally, deletion of Hif1α increased alkaline phosphatase (ALP) positive colonies and mineral deposits in Hif1αKO cultures compared to Ctr cells, and led to a 30% reduction in Fgf23 expression. In contrast, Hif1αTg cells showed reduced osteogenic potential, with fewer ALP colonies and mineral deposits, and a 2-fold increase in Fgf23 expression.

Conclusion

Our data suggest that osseous HIF1α stimulates FGF23 production in CKD and is a negative regulator of osteoblast differentiation and function. Thus, inhibition of HIF1α in bone might represent a novel therapeutic strategy to improve bone and mineral outcomes in CKD.

Funding

  • NIDDK Support