# Role of Pulmonary Osteoclast-Like Cells in Lung Injury

> **NIH VA I01** · CINCINNATI VA MEDICAL CENTER RESEARCH · 2021 · —

## Abstract

This proposal explores the role of a pulmonary osteoclast-like cell (POLC) in asbestos-induced pulmonary fibrosis.
We first discovered POLCs while studying pulmonary alveolar microlithiasis (PAM), a rare, autosomal recessive
disorder caused by mutations in the epithelial sodium phosphate co-transporter, Npt2b. Phosphate accumulates
in the alveolar lining fluid and complexes with calcium to form spherical hydroxyapatite microliths containing bone
matrix proteins and surfactant components. Contact of microliths with alveolar macrophages (AM) and recruited
alveolar monocytes (Alv-Mo) induces osteoclastic transformation, with expression of the full repertoire of
osteoclast signature genes and proteins in multinucleated giant cells (MNGC) including tartrate resistant acid
phosphatase (TRAP), cathepsin K (CTSK), and the proton pump ATP6V0D2. Single cell RNA sequencing of
human PAM lung also confirmed a robust osteoclast signature in AM, and IHC confirmed the presence of TRAP
and CTSK positive MNGC. Like humans, Npt2b-/- animals develop modest pulmonary fibrosis and a marked
restrictive physiologic defect. We found that microliths induce alveolar expression of the requisite
osteoclastogenic cytokines, mCSF and RANKL, for POLC differentiation and expression of hydrochloric acid and
CTSK that both dissolve stones and damage tissues. We also found that when microliths were adoptively
transferred into the lungs of WT animals, they attached to or were degraded by macrophages, and were cleared
within 28d without residual inflammation or fibrosis or evidence of lung injury. We noted that hyperdense infiltrates
in our index PAM patient progressed rapidly when she was placed on bisphosphonates, and that anti-RANKL
therapy slowed the clearance of microliths in Npt2b-/- mice. These data led us to the conclusion that osteoclastic
transformation of AM and Alv-Mo is the lung's primary defense against microliths and that it may represent a
stereotypic response to other particles, including asbestos. Indeed, we find that asbestos challenge is also
associated with TRAP and CTSK expression in myeloid cells and MNGC in the BAL and lung tissue, and that it
culminates in destructive remodeling and pulmonary fibrosis. The BAL cells from asbestos but not saline treated
mice degrade bone and liberate collagen fragments from the bone matrix when plated on bovine bone slices, the
signature function of osteoclasts. The differential tissue responses of complete healing vs. fibrosis to dissolvable
(microliths) vs. persistent (asbestos) particulates forms the basis for our hypothesis that acid and matrix degrading
enzymes produced by POLCs may be primary drivers of fibrosis when the inhaled particle is invincible. To test
this hypothesis in three aims, we will determine; 1) the gene programs that underlie pulmonary osteoclastic
specification of recruited monocytes in response to asbestos, 2) the osteoclast functions acquired by monocytes
and macrophages upon asbestos challenge, 3) t...

## Key facts

- **NIH application ID:** 10115416
- **Project number:** 1I01BX005128-01A1
- **Recipient organization:** CINCINNATI VA MEDICAL CENTER RESEARCH
- **Principal Investigator:** Francis Xavier McCormack
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2021-05-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10115416

## Citation

> US National Institutes of Health, RePORTER application 10115416, Role of Pulmonary Osteoclast-Like Cells in Lung Injury (1I01BX005128-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10115416. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*