Bone-derived C-terminal FGF23 cleaved peptides increase iron availability in acute inflammation

Area of Science:

• Biochemistry
• Endocrinology
• Mineral Metabolism

Background:

• Inflammation causes functional iron deficiency by increasing hepcidin, a key regulator of iron metabolism.
• Fibroblast growth factor 23 (FGF23) production and cleavage are altered during inflammation, leading to excess C-terminal FGF23 (Cter-FGF23) peptides.

Purpose of the Study:

• To investigate the role of osteocyte-derived Cter-FGF23 in regulating hepcidin and iron metabolism during acute inflammation.
• To determine if Cter-FGF23 directly influences hepcidin expression and iron levels.

Main Methods:

• Utilized genetically modified mice with osteocyte-specific deletion of Fgf23 or impaired FGF23 cleavage (Furin deletion).
• Assessed Cter-FGF23 levels, hepcidin expression (Hamp mRNA), and serum iron concentrations in inflamed and control mice.
• Investigated the interaction between Cter-FGF23 and bone morphogenetic proteins (BMPs) in vitro and in vivo.

Main Results:

• Osteocyte-specific Fgf23 deletion significantly reduced Cter-FGF23 levels during inflammation, exacerbating iron deficiency due to increased hepcidin.
• Impaired FGF23 cleavage also led to reduced Cter-FGF23 and altered iron homeostasis.
• Cter-FGF23 peptides bind BMP2 and BMP9, inhibiting their hepcidin-inducing activity and normalizing serum iron levels.

Conclusions:

• Bone, specifically osteocytes, is a major source of Cter-FGF23 during inflammation.
• Cter-FGF23 acts independently of intact FGF23 (iFGF23) to modulate BMP-induced hepcidin secretion in the liver.
• Cter-FGF23 plays a critical role in regulating iron metabolism during inflammatory states by counteracting hepcidin induction.