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Kidney to bone via bedside to bench…and back?
Alexander Grabner1, Myles Wolf1,2
1Division of Nephrology, Department of Medicine, and.
Abstract:
The rapid rise in circulating fibroblast growth factor 23 (FGF23) associated with kidney injury results in calcitriol deficiency, altered calcium homeostasis, and secondary hyperparathyroidism, and may contribute to cardiovascular complications and death. However, the mechanisms of increased FGF23 in states of kidney injury remain unclear. In this issue of the JCI, Simic et al. screened plasma taken from the renal vein of patients undergoing cardiac catheterization and identified glycerol-3-phosphate (G-3-P) as the most significant correlate of simultaneous arterial FGF23 levels. When G-3-P was administered to mice, FGF23 production increased in bone. In a series of elegant mouse studies, the authors discovered a pathway linking increased G-3-P to increased FGF23 via increases in lysophosphatidic acid (LPA), which activates the LPA receptor 1 in FGF23-secreting cells in the bone and bone marrow. Although the authors present human data that broadly support the results from the mouse models, further research is needed to determine whether targeting the G-3-P/FGF23 pathway has the potential to modify FGF23-related complications in the clinic.
Insights
Kidney injury elevates fibroblast growth factor 23 (FGF23), leading to complications. Researchers found glycerol-3-phosphate (G-3-P) links kidney injury to increased FGF23 via lysophosphatidic acid (LPA).
Area of Science:
- Nephrology
- Endocrinology
- Cardiovascular Medicine
Background:
- Elevated fibroblast growth factor 23 (FGF23) in kidney injury causes mineral imbalance and cardiovascular risks.
- The precise mechanisms driving FGF23 elevation during kidney injury are not fully understood.
Purpose of the Study:
- To elucidate the pathway linking kidney injury to increased FGF23 levels.
- To identify key molecular mediators involved in FGF23 regulation.
Main Methods:
- Screening of plasma from renal vein catheterization patients to identify FGF23 correlates.
- Administration of glycerol-3-phosphate (G-3-P) to mouse models.
- Investigating the role of lysophosphatidic acid (LPA) and its receptor in FGF23 production.
Main Results:
- Glycerol-3-phosphate (G-3-P) emerged as a significant correlate of arterial FGF23 levels.
- G-3-P administration increased FGF23 production in mouse bone.
- A pathway involving G-3-P, lysophosphatidic acid (LPA), and LPA receptor 1 was identified, stimulating FGF23 secretion from bone and bone marrow cells.
Conclusions:
- The study identifies a novel pathway (G-3-P/LPA/LPA receptor 1) contributing to FGF23 elevation in kidney injury.
- Human data broadly support the findings from mouse models.
- Further research is warranted to explore therapeutic targeting of this pathway for FGF23-related complications.
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