Insights into pulmonary phosphate homeostasis and osteoclastogenesis emerge from the study of pulmonary alveolar microlithiasis.
Insights into pulmonary phosphate homeostasis and osteoclastogenesis emerge from the study of pulmonary alveolar microlithiasis.
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DOI：
10.1038/s41467-023-36810-8
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发表时间：
2023-03-02
影响因子：
16.6
通讯作者：
McCormack, Francis X.
中科院分区：
文献类型：
--
作者：
Uehara, Yasuaki;Tanaka, Yusuke;Zhao, Shuyang;Nikolaidis, Nikolaos M.;Pitstick, Lori B.;Wu, Huixing;Yu, Jane J.;Zhang, Erik;Hasegawa, Yoshihiro;Noel, John G.;Gardner, Jason C.;Kopras, Elizabeth J.;Haffey, Wendy D.;Greis, Kenneth D.;Guo, Jinbang;Woods, Jason C.;Wikenheiser-Brokamp, Kathryn A.;Kyle, Jennifer E.;Ansong, Charles;Teitelbaum, Steven L.;Inoue, Yoshikazu;Altinisik, Goksel;Xu, Yan;McCormack, Francis X.
肺泡微石症是一种常染色体隐性肺部疾病，由肺上皮Npt2b钠-磷酸钠共转运蛋白缺乏引起，导致磷酸盐积聚并在肺泡间隙形成羟基磷灰石微石。肺泡微石症肺外植体的单细胞转录组学分析显示，肺泡单核细胞中存在强大的破骨细胞基因特征，并且发现磷酸钙微石含有丰富的蛋白质和脂质基质，其中包括骨吸收破骨细胞酶和其他蛋白质，这表明破骨细胞样细胞在宿主对微石的反应中起作用。在研究微石清除的机制时，我们发现Npt2b通过对替代磷酸盐转运蛋白活性和肺泡骨保护素的影响来调节肺磷酸盐稳态，并且微石以核因子-κB配体受体激活剂和饮食磷酸盐依赖的方式诱导破骨细胞的形成和激活。这项工作揭示了Npt2b和肺破骨细胞样细胞在肺稳态中起关键作用，并为治疗肺部疾病提供了潜在的新治疗靶点。破骨细胞来源于循环骨髓细胞，介导骨修复、维持和重塑。在这里，作者表明，肺也招募并重新编程单核细胞和肺泡巨噬细胞为破骨细胞样细胞，以清除空气中的致病颗粒。
Pulmonary alveolar microlithiasis is an autosomal recessive lung disease caused by a deficiency in the pulmonary epithelial Npt2b sodium-phosphate co-transporter that results in accumulation of phosphate and formation of hydroxyapatite microliths in the alveolar space. The single cell transcriptomic analysis of a pulmonary alveolar microlithiasis lung explant showing a robust osteoclast gene signature in alveolar monocytes and the finding that calcium phosphate microliths contain a rich protein and lipid matrix that includes bone resorbing osteoclast enzymes and other proteins suggested a role for osteoclast-like cells in the host response to microliths. While investigating the mechanisms of microlith clearance, we found that Npt2b modulates pulmonary phosphate homeostasis through effects on alternative phosphate transporter activity and alveolar osteoprotegerin, and that microliths induce osteoclast formation and activation in a receptor activator of nuclear factor-κB ligand and dietary phosphate dependent manner. This work reveals that Npt2b and pulmonary osteoclast-like cells play key roles in pulmonary homeostasis and suggest potential new therapeutic targets for the treatment of lung disease. Osteoclasts are derived from circulating myeloid cells to mediate bone repair, maintenance and remodeling. Here, the authors show that the lung also recruits and reprograms monocytes and alveolar macrophages into osteoclast-like cells to clear pathogenic particles from the airspace.
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