Abstract
Fibroblast growth factor-23 (FGF23), a bone-produced hormone, plays a critical role in mineral homeostasis. Human diseases associated with excessive intact circulating FGF23 (iFGF23) result in hypophosphatemia and low vitamin D hormone in patients with normal kidney function. In addition, there is accumulating evidence linking FGF23 with inflammation. Based on these studies and the frequent observation of hypophosphatemia among septic patients, we sought to elucidate further the relationship between FGF23 and mineral homeostasis in a clinically relevant murine polymicrobial sepsis model. Medium-severity sepsis was induced by cecum ligation puncture (CLP) in adult CD-1 mice of both sexes. Healthy CD-1 mice (without CLP) were used as controls. Forty-eight hours post-CLP, spontaneous urine was collected, and serum, organs and bones were sampled at necropsy. Serum iFGF23 increased ~20-fold in CLP compared to control mice. FGF23 protein concentration was increased in the bones, but not in spleen or liver of CLP mice. Despite the ~20-fold iFGF23 increase, we did not observe any significant changes in mineral homeostasis or parathyroid hormone levels in the blood of CLP animals. Urinary excretion of phosphate, calcium, and sodium remained unchanged in male CLP mice, whereas female CLP mice exhibited lower urinary calcium excretion, relative to healthy controls. In line with renal FGF23 resistance, expression of phosphate-, calcium- and sodium-transporting proteins did not show consistent changes in the kidneys of male and female CLP mice. Renal expression of the co-receptor αKlotho was downregulated in female, but not in male CLP mice. In conclusion, our data demonstrate that the dramatic, sex-independent rise in serum iFGF23 post-CLP was mainly caused by an upregulation of FGF23 secretion in the bone. Surprisingly, the upsurge in circulating iFGF23 did not alter humoral mineral homeostasis in the acutely septic mice. Hence, the biological function of elevated FGF23 in sepsis remains unclear and warrants further studies.
Highlights
While we found a dramatic increase in circulating intact FGF23 (iFGF23) in mice of both sexes after cecum ligation puncture (CLP), this change did not translate into major abnormalities of mineral homeostasis
When we measured iFGF23 serum concentration using a different assay (Kainos) compared with Fig 1 (Immutopics) in samples that were less diluted, we found the serum iFGF23 level (Fig 2) ~20-fold upregulated in CLP mice of both sexes vs. healthy controls, 48 h after CLP
To identify the major source of increased circulating Fibroblast growth factor 23 (FGF23) in our CLP model, we examined the abundance of intact FGF23 in spleen, liver, and bone (Fig 2)
Summary
Fibroblast growth factor 23 (FGF23) is a 32 kDa glycoprotein mainly synthesized by osteoblast and osteocytes [1,2,3,4] in response to elevated serum phosphate [5,6,7,8,9], calcium [8], vitamin D [6,10,11] and parathyroid hormone (PTH) [12,13,14,15,16]. Masuda et al identified activated dendritic cells and macrophages as source of the LPS-induced rise in splenic FGF23 expression This observation was corroborated by Bansal et al who attributed the elevation of circulating Fgf in LPS-treated mice to an increase in splenic Fgf transcription [41]. CLP is considered the gold standard [46,47] in sepsis modeling since the resulting polymicrobial sepsis closely recapitulates the features of human abdominal sepsis [48,49] Using this model, we analyzed circulating intact FGF23 (iFGF23), mineral homeostasis, as well as FGF23 production in the bone, spleen and FGF23 and polymicrobial sepsis liver of male and female mice. FGF23 protein expression was upregulated in the bone, but not in the spleen and liver of septic mice
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