Bone-derived C-terminal FGF23 cleaved peptides increase iron availability in acute inflammation.
Bone-derived C-terminal FGF23 cleaved peptides increase iron availability in acute inflammation.
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DOI：
10.1182/blood.2022018475
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发表时间：
2023-07-06
期刊：
影响因子：
20.3
通讯作者：
David, Valentin
中科院分区：
文献类型：
--
作者：
Courbon, Guillaume;Thomas, Jane Joy;Martinez-Calle, Marta;Wang, Xueyan;Spindler, Jadeah;Von Drasek, John;Hunt-Tobey, Bridget;Mehta, Rupal;Isakova, Tamara;Chang, Wenhan;Creemers, John W. M.;Ji, Peng;Martin, Aline;David, Valentin
骨细胞是急性炎症中Cter-FGF23肽的主要来源。骨源性 Cter-FGF23 肽是铁保守分子，可拮抗 BMP 诱导的铁调素产生。炎症通过增加肝铁调节肽铁调素的表达而导致功能性缺铁。炎症还通过增加 Fgf23 转录和 FGF23 裂解来刺激成纤维细胞生长因子 23 (FGF23) 的产生，这矛盾地导致 C 端 FGF23 肽 (Cter-FGF23) 而非完整的 FGF23 (iFGF23) 激素过量。我们确定 Cter-FGF23 的主要来源是骨细胞，并研究了 Cter-FGF23 肽是否在响应急性炎症的铁调素和铁代谢调节中发挥直接作用。携带骨细胞特异性 Fgf23 缺失的小鼠在急性炎症期间 Cter-FGF23 水平降低约 90%。由于铁调素产生过多，Cter-FGF23 的减少导致发炎小鼠的循环铁进一步减少。我们在小鼠中观察到了类似的结果，由于骨细胞特异性删除弗林蛋白酶，FGF23 裂解受损。接下来，我们证明 Cter-FGF23 肽与骨形态发生蛋白 (BMP) 家族的成员 BMP2 和 BMP9 结合，它们是铁调素的既定诱导剂。 Cter-FGF23 和 BMP2 或 BMP9 的共同给药可阻止 BMP2/9 诱导的 Hamp 信使 RNA 和循环铁调素水平的增加，从而导致血清铁水平正常。最后，在发炎的 Fgf23KO 小鼠中注射 Cter-FGF23 以及在野生型小鼠中基因过度表达 Cter-Fgf23 也导致铁调素降低和循环铁水平升高。总之，在炎症期间，骨是 Cter-FGF23 分泌的主要来源，并且独立于 iFGF23，Cter-FGF23 减少肝脏中 BMP 诱导的铁调素分泌。炎症与铁调素表达增加有关，从而导致功能性铁缺乏。炎症还会刺激成纤维细胞生长因子 23 (FGF23) 的表达，尽管 FGF23 的大部分被裂解并且不能发挥完整激素的作用。 Courbon 等人通过证明 FGF23 片段与骨形态发生蛋白 (BMP) 受体结合，阻断 BMP 诱导铁调素表达，将这两个观察结果联系起来。通过这种方式，FGF23 片段充当负反馈回路来调节铁调素的诱导。
Osteocytes are the main source of Cter-FGF23 peptides in acute inflammation. Bone-derived Cter-FGF23 peptides are iron conserving molecules and antagonize BMP-induced hepcidin production. Inflammation leads to functional iron deficiency by increasing the expression of the hepatic iron regulatory peptide hepcidin. Inflammation also stimulates fibroblast growth factor 23 (FGF23) production by increasing both Fgf23 transcription and FGF23 cleavage, which paradoxically leads to excess in C-terminal FGF23 peptides (Cter-FGF23), rather than intact FGF23 (iFGF23) hormone. We determined that the major source of Cter-FGF23 is osteocytes and investigated whether Cter-FGF23 peptides play a direct role in the regulation of hepcidin and iron metabolism in response to acute inflammation. Mice harboring an osteocyte-specific deletion of Fgf23 showed a ∼90% reduction in Cter-FGF23 levels during acute inflammation. Reduction in Cter-FGF23 led to a further decrease in circulating iron in inflamed mice owing to excessive hepcidin production. We observed similar results in mice showing impaired FGF23 cleavage owing to osteocyte-specific deletion of Furin. We next showed that Cter-FGF23 peptides bind members of the bone morphogenetic protein (BMP) family, BMP2 and BMP9, which are established inducers of hepcidin. Coadministration of Cter-FGF23 and BMP2 or BMP9 prevented the increase in Hamp messenger RNA and circulating hepcidin levels induced by BMP2/9, resulting in normal serum iron levels. Finally, injection of Cter-FGF23 in inflamed Fgf23KO mice and genetic overexpression of Cter-Fgf23 in wild type mice also resulted in lower hepcidin and higher circulating iron levels. In conclusion, during inflammation, bone is the major source of Cter-FGF23 secretion, and independently of iFGF23, Cter-FGF23 reduces BMP-induced hepcidin secretion in the liver. Inflammation is associated with increased hepcidin expression, which leads to functional iron deficiency. Inflammation also stimulates expression of fibroblast growth factor 23 (FGF23), although much of FGF23 is cleaved and does not function as an intact hormone. Courbon et al link these 2 observations by demonstrating that FGF23 fragments bind to bone morphogenetic protein (BMP) receptors, blocking BMP induction of hepcidin expression. In this way, FGF23 fragments act as a negative feedback loop to moderate the induction of hepcidin.
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影响因子：
4
作者：
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10.1
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影响因子：
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影响因子：
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