Silicosis is a life-threatening, progressive lung disease limited by a poor understanding of pathophysiology and a lack of effective treatments. We explored the mechanisms of silica-induced pulmonary fibrosis in a mouse model using multiple modalities including whole-lung single-nucleus RNA sequencing. Silica particles were administered via the i.t. route into the lungs of C57BL/6 mice. Lung fibrosis in tissues from silicosis patients and silica-challenged mice was characterized, using fibrosis-related gene expression quantified by RT-qPCR, hydroxyproline measured in lung homogenates, and lung compliance measured using oscillatory impedance. To explore novel mechanisms of silica-induced fibrosis, single nucleus RNA-sequencing was conducted on longitudinally collected whole lung samples. To validate these findings, the presence of osteoclast-like cells and osteoclast differentiation in human and mouse lung tissues was interrogated with RT-qPCR, immunohistochemistry, biomarker analysis, and osteoclast functional assays. Cytokines known to participate in osteoclast differentiation were measured in BALF by ELISA. The finding that silica exposure induced regional expression of the signature osteoclastogenic cytokine, RANKL, led to a search for the source. Increased RANKL protein expression was identified after silica challenge in isolated AT2 and lymphocytes by ELISA and flow cytometry. The propensity of cultured BAL cells isolated from mice before and after silica challenge was tested by determining the threshold of RANKL concentration required for robust, multinucleated osteoclast formation. Fibrosis assessed silica-challenged mice treated with anti-RANKL by the i.p. route using histology, RT-qPCR, hydroxyproline assay, and pulmonary function testing. Because the silica-challenged animals were easily distinguished from controls based on the presence of particles in lung tissue, randomization and blinding were not used for experiments with animals, but mice were age- and -sex matched for all studies. The experimental procedures were approved by the Institutional Animal Care and Use Committee at the University of Cincinnati.