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...