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

2022 Fiscal Year Final Research Report

• Project/Area Number: 21K16144
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53030:Respiratory medicine-related
• Research Institution: Sapporo Medical University
• Principal Investigator: Uehara Yasuaki 札幌医科大学, 医学部, 助教 (40882907)
• Project Period (FY): 2021-04-01 – 2023-03-31
• Keywords: 肺胞微石症 / Npt2b / RANKL / 破骨細胞 / OPG

Outline of Final Research Achievements

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.

Free Research Field

呼吸器内科

Academic Significance and Societal Importance of the Research Achievements

本研究では肺胞微石症における破骨細胞様細胞の解析を通じて、肺における破骨細胞様多核巨細胞の分化の機序や機能、さらに肺胞微石症の病態や微石のクリアランスへの影響を解明した。これらの研究結果は破骨細胞様多核巨細胞の機能に基づいた肺胞微石症の新たな治療開発の糸口となると考えられる。また珪肺やアスベスト肺、サルコイドーシス肺の肉芽腫病変などでも多核巨細胞は報告されておりそれらの呼吸器疾患の病態の解明や治療法の開発への応用も期待できる。