Calciprotein particles regulate fibroblast growth factor-23 expression in osteoblasts
Calciprotein particles regulate fibroblast growth factor-23 expression in osteoblasts
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DOI：
10.1016/j.kint.2019.10.019
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发表时间：
2020-04-01
影响因子：
19.6
通讯作者：
Kuro-o, Makoto
中科院分区：
文献类型：
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作者：
Akiyama, Ken-ichi;Miura, Yutaka;Kuro-o, Makoto
成纤维细胞生长因子-23(FGF23)是维持磷酸盐稳态所必需的激素。作为对磷酸盐摄入的反应，FGF23由骨细胞/成骨细胞分泌，并作用于肾脏，增加尿磷排泄。然而，这些细胞感知磷酸盐摄取的机制仍然不清楚。钙蛋白颗粒是钙-磷酸沉淀物与血清胎球蛋白-A结合的纳米颗粒，在含有钙、磷和胎球蛋白-A的溶液中自发生成，以胶体形式分散。在培养的成骨细胞中，培养液中钙或磷浓度的增加都会诱导FGF23的表达，这依赖于钙蛋白颗粒的形成。当钙磷沉淀物从非晶相向晶相的转变被双膦酸盐阻断时，钙蛋白颗粒尺寸变小，FGF23的表达增加，这表明含有无定形磷酸钙沉淀物的小颗粒钙蛋白比含有结晶性磷酸钙沉淀物的大颗粒钙蛋白颗粒具有更强的FGF23诱导作用。在小鼠中，口服磷酸盐片剂可短暂增加循环钙蛋白颗粒水平，随后FGF23表达和血清FGF23水平略有增加。然而，持续的膳食磷负荷导致循环钙蛋白颗粒和FGF23水平持续而强劲地增加。我们通过体内成像证实，静脉注射的钙蛋白颗粒渗入骨髓并沉积在骨的内表面，表明这些颗粒直接接触成骨细胞。因此，我们认为成骨细胞在摄取磷酸盐后感觉到细胞外钙蛋白颗粒增加时，会诱导FGF23的表达和分泌。
Fibroblast growth factor-23 (FGF23) is a hormone indispensable for maintaining phosphate homeostasis. In response to phosphate intake, FGF23 is secreted from osteocytes/osteoblasts and acts on the kidney to increase urinary phosphate excretion. However, the mechanism by which these cells sense phosphate intake remains elusive. Calciprotein particles are nanoparticles of calcium-phosphate precipitates bound to serum protein fetuin-A and are generated spontaneously in solution containing calcium, phosphate, and fetuin-A to be dispersed as colloids. In cultured osteoblastic cells, increase in either calcium or phosphate concentration in the medium induced FGF23 expression, which was dependent on calciprotein particle formation. When transition of calcium-phosphate precipitates from the amorphous phase to the crystalline phase was blocked by bisphosphonate, the calciprotein particle size was reduced and FGF23 expression was augmented, suggesting that small calciprotein particles containing amorphous calcium-phosphate precipitates function as a more potent FGF23 inducer than larger calciprotein particles containing crystalline calcium-phosphate precipitates. In mice, bolus phosphate administration by oral gavage transiently increased circulating calciprotein particle levels followed by a modest increase in FGF23 expression and serum FGF23 levels. However, continuous dietary phosphate load induced robust and persistent increase in circulating calciprotein particles and FGF23 levels. We confirmed by in vivo imaging that calciprotein particles injected intravenously extravasated into the bone marrow and were deposited on the inner surface of the bone, indicating that these particles have direct access to osteoblasts. Thus, we propose that osteoblasts induce FGF23 expression and secretion when they sense an increase in extracellular calciprotein particles following phosphate ingestion.