van Vuren Annelies J, Gaillard Carlo A J M, Eisenga Michele F, van Wijk Richard, van Beers Eduard J
Van Creveldkliniek, Department of Internal Medicine and Dermatology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.
Department of Internal Medicine and Dermatology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.
Front Physiol. 2019 Mar 26;10:304. doi: 10.3389/fphys.2019.00304. eCollection 2019.
We provide an overview of the evidence for an erythropoietin-fibroblast growth factor 23 (FGF23) signaling pathway directly influencing erythroid cells in the bone marrow. We outline its importance for red blood cell production, which might add, among others, to the understanding of bone marrow responses to endogenous erythropoietin in rare hereditary anemias. FGF23 is a hormone that is mainly known as the core regulator of phosphate and vitamin D metabolism and it has been recognized as an important regulator of bone mineralization. Osseous tissue has been regarded as the major source of FGF23. Interestingly, erythroid progenitor cells highly express FGF23 protein and carry the FGF receptor. This implies that erythroid progenitor cells could be a prime target in FGF23 biology. FGF23 is formed as an intact, biologically active protein (iFGF23) and proteolytic cleavage results in the formation of the presumed inactive C-terminal tail of FGF23 (cFGF23). FGF23-knockout or injection of an iFGF23 blocking peptide in mice results in increased erythropoiesis, reduced erythroid cell apoptosis and elevated renal and bone marrow erythropoietin mRNA expression with increased levels of circulating erythropoietin. By competitive inhibition, a relative increase in cFGF23 compared to iFGF23 results in reduced FGF23 receptor signaling and mimics the positive effects of FGF23-knockout or iFGF23 blocking peptide. Injection of recombinant erythropoietin increases FGF23 mRNA expression in the bone marrow with a concomitant increase in circulating FGF23 protein. However, erythropoietin also augments iFGF23 cleavage, thereby decreasing the iFGF23 to cFGF23 ratio. Therefore, the net result of erythropoietin is a reduction of iFGF23 to cFGF23 ratio, which inhibits the effects of iFGF23 on erythropoiesis and erythropoietin production. Elucidation of the EPO-FGF23 signaling pathway and its downstream signaling in hereditary anemias with chronic hemolysis or ineffective erythropoiesis adds to the understanding of the pathophysiology of these diseases and its complications; in addition, it provides promising new targets for treatment downstream of erythropoietin in the signaling cascade.
我们概述了促红细胞生成素-成纤维细胞生长因子23（FGF23）信号通路直接影响骨髓中红细胞系细胞的证据。我们概述了其对红细胞生成的重要性，这可能有助于，尤其是在理解罕见遗传性贫血中骨髓对内源性促红细胞生成素的反应方面。FGF23是一种主要作为磷酸盐和维生素D代谢核心调节因子而为人所知的激素，并且它已被认为是骨矿化的重要调节因子。骨组织一直被视为FGF23的主要来源。有趣的是，红系祖细胞高度表达FGF23蛋白并携带FGF受体。这意味着红系祖细胞可能是FGF23生物学中的主要靶点。FGF23以完整的、具有生物活性的蛋白（iFGF23）形式形成，蛋白水解切割导致形成推测无活性的FGF23 C末端尾巴（cFGF23）。在小鼠中敲除FGF23或注射iFGF23阻断肽会导致红细胞生成增加、红系细胞凋亡减少以及肾脏和骨髓促红细胞生成素mRNA表达升高，同时循环促红细胞生成素水平增加。通过竞争性抑制，与iFGF23相比，cFGF23相对增加会导致FGF23受体信号传导减少，并模拟FGF23敲除或iFGF23阻断肽的积极作用。注射重组促红细胞生成素会增加骨髓中FGF23 mRNA表达，同时循环FGF23蛋白也会增加。然而，促红细胞生成素也会增强iFGF23的切割，从而降低iFGF23与cFGF23的比例。因此，促红细胞生成素的最终结果是iFGF23与cFGF23比例降低，这会抑制iFGF23对红细胞生成和促红细胞生成素产生的影响。阐明促红细胞生成素-FGF23信号通路及其在伴有慢性溶血或无效红细胞生成的遗传性贫血中的下游信号传导，有助于理解这些疾病及其并发症的病理生理学；此外，它为信号级联中促红细胞生成素下游的治疗提供了有前景的新靶点。
