Role of RANKL in Alveolar Epithelial Cell Regeneration: Potential Novel Contributor to Lung Tissue Repair

Receptor activator for NF-κβ (RANK) ligand (RANKL) is found in lung tissue and elevated in lung diseases like chronic obstructive pulmonary disease (COPD), cystic fibrosis and silica-induced pulmonary fibrosis. RANKL is a well-known stimulator of bone tissue degradation, which may explain the association between these lung diseases and osteoporosis. However, RANKL is also reported to be involved in epithelial cell regeneration in breast and thymus. We hypothesized that RANKL, which is produced directly in lung tissue, is involved in the regeneration of lung epithelial cells. Therefore, we aimed to clarify the specific role of RANKL in this process. Using an organoid model of lung epithelial development by co-culturing primary EpCAM+ lung epithelial cells with fibroblasts, we found higher numbers of alveolar organoids after soluble RANKL treatment compared to control. Importantly, this effect was similar in human RANKL-treated organoids derived from epithelial cells isolated from lung tissue of COPD patients. The effect of RANKL was abrogated upon addition of osteoprotegerin, the soluble inhibitor of RANKL. We also found that RANKL stimulated phosphorylation of Akt suggesting involvement of its receptor RANK in the signaling pathway. Moreover, in vivo RANKL administration resulted in more type II alveolar epithelial cells in lungs of mice with silica-induced pulmonary fibrosis. In conclusion, we found that RANKL promotes type II alveolar epithelial cell regeneration and may therefore be a novel contributor to lung tissue repair. New and Noteworthy Our study provides compelling evidence demonstrating an as of yet unknown function of receptor activator for NF-κβ ligand (RANKL) in lung tissue regeneration. We found that RANKL plays a role in the regeneration of lung epithelial cells, particularly type II alveolar epithelial cells. This may also have clinical implications as promotion of alveolar epithelial cell regeneration may enhance lung tissue repair, an important target in patients with lung diseases like COPD and fibrosis. ### Competing Interest Statement The authors have declared no competing interest.