Kidney Week

Abstract: FR-PO505

Osteocytes Are the Major Source of Circulating FGF23 During Acute Inflammation

Session Information

• Bone and Mineral Metabolism: Basic
  October 26, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Bone and Mineral Metabolism

• 401 Bone and Mineral Metabolism: Basic

Authors

• Courbon, Guillaume, Northwestern University - Feinberg School of Medicine, Chicago, Illinois, United States

Guillaume Courbon,

• Gerber, Claire, Northwestern University - Feinberg School of Medicine, Chicago, Illinois, United States

Claire Gerber,

• Neuburg, Samantha, Northwestern University - Feinberg School of Medicine, Chicago, Illinois, United States

Samantha Neuburg,

• Capella, Maralee, Northwestern University - Feinberg School of Medicine, Chicago, Illinois, United States

Maralee Capella,

• Dussold, Corey, Northwestern University - Feinberg School of Medicine, Chicago, Illinois, United States

Corey Dussold,

• Wang, Xueyan, Northwestern University - Feinberg School of Medicine, Chicago, Illinois, United States

Xueyan Wang,

• Qi, Lixin, Northwestern University - Feinberg School of Medicine, Chicago, Illinois, United States

Lixin Qi,

• Chang, Wenhan, Endocrine Unit, SF-VAMC, University of California San Francisco, San Francisco, California, United States

Wenhan Chang,

• Wolf, Myles, Duke University, Durham, North Carolina, United States

Myles Wolf,

• Martin, Aline, Northwestern University - Feinberg School of Medicine, Chicago, Illinois, United States

Aline Martin,

• David, Valentin, Northwestern University - Feinberg School of Medicine, Chicago, Illinois, United States

Valentin David,

Background

Inflammation is a novel mechanism that stimulates fibroblast growth factor (FGF) 23 production in bone cells and extraosseous tissues, however the contribution of osteocytes to circulating FGF23 levels during acute inflammation is unknown.

Methods

To investigate the effects of inflammation on FGF23 production, wild-type (WT) mice and mice with a conditional deletion (cKO) of Fgf23 in osteocytes (Fgf23fl/fl;DMP1-Cre+) received a single injection of interleukin-1β (IL-1β) or saline (Ctr). We measured FGF23 mRNA and circulating intact and total protein (cFGF23 which includes intact and cleaved proteins) up to 6 hours post injection.

Results

In WT mice, injection of IL-1β increased circulating levels of intact and total FGF23 (12-fold and 62-fold, respectively, p<0.001 vs Ctr). IL-1β increased Fgf23 mRNA expression by 60 fold in bone, 7 fold in spleen and by 300 fold in kidney (p<0.05 vs. Ctr), suggesting that extraosseous production of FGF23 may contribute to circulating FGF23 levels. In line with these findings, cKO-Ctr mice did not show a significant reduction in circulating FGF23 compared to WT-Ctr mice, suggesting that extraosseous FGF23 production is sufficient to maintain relatively normal circulating FGF23 levels. However, cKO mice showed a markedly reduced FGF23 secretion in response to IL-1β injection compared to WT- IL-1β mice for both intact (-80%) and total FGF23 (-92%, p<0.001). Consistent with these data, bone Fgf23 mRNA and protein expression levels were also dramatically reduced by 80% (p<0.01) in cKO- IL-1β mice compared to WT- IL-1β. Finally, IL-1β treatment of primary osteocytes cultures from WT and cKO animals increased Fgf23 mRNA expression and protein secretion by 10 fold in WT mice (p<0.05 vs. Ctr) but failed to increase FGF23 in cKO cultures.

Conclusion

These results suggest that Fgf23 expression is increased in bone and extraskeletal tissues during acute inflammation, however osteocytes are the major secretory source for the circulating FGF23 protein.

Funding

• NIDDK Support