Insights into pulmonary phosphate homeostasis and osteoclastogenesis emerge from the study of pulmonary alveolar microlithiasis

Yasuaki Uehara, Yusuke Tanaka, Shuyang Zhao, Nikolaos M. Nikolaidis, Lori B. Pitstick, Huixing Wu, Jane J. Yu, Erik Zhang, Yoshihiro Hasegawa, John G. Noel, Jason C. Gardner, Elizabeth J. Kopras, Wendy D. Haffey, Kenneth D. Greis, Jinbang Guo, Jason C. Woods, Kathryn A. Wikenheiser-Brokamp, Jennifer E. Kyle, Charles Ansong, Steven L. TeitelbaumYoshikazu Inoue, Göksel Altinişik, Yan Xu, Francis X. McCormack

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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.

Original languageEnglish
Article number1205
JournalNature communications
Volume14
Issue number1
DOIs
StatePublished - Dec 2023

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