Author:
Uehara Yasuaki,Nikolaidis Nikolaos M.,Pitstick Lori B.,Wu Huixing,Yu Jane J.,Zhang Erik,Hasegawa Yoshihiro,Tanaka Yusuke,Noel John G.,Gardner Jason C.,Kopras Elizabeth J.,Haffey Wendy D.,Greis Kenneth D.,Guo Jinbang,Woods Jason C.,Wikenheiser-Brokamp Kathryn A.,Zhao Shuyang,Xu Yan,Kyle Jennifer E.,Ansong Charles,Teitelbaum Steven L.,Inoue Yoshikazu,Altinişik Göksel,McCormack Francis X.
Abstract
AbstractPulmonary alveolar microlithiasis (PAM) 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 PAM 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 suggested a role for osteoclast-like cells in the defense against 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 activity in a receptor activator of nuclear factor-κB ligand (RANKL) 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.
Publisher
Cold Spring Harbor Laboratory