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

Abstract

Receptor activator for NF-kappa beta (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.

Osteoprotegerin is an early marker of the fibrotic process and of antifibrotic treatment responses in ex vivo lung fibrosis

“…However, in recent years, an increasing number of studies have shown correlations between OPG and several brotic conditions including liver, vascular, cardiac, kidney and intestinal brosis [18][19][20][21][22]. This study, and our own previous studies [9,10] have now shown that this also appears to be the case for brosis in lung tissue and even wound healing. Our data shows that after the slicing procedure a repair or regenerative response was induced, with higher Col1α1 and Fn mRNA expression, which was accompanied by higher production of OPG.…”

“…We recently described a novel marker called osteoprotegerin (OPG) that is highly upregulated in lung tissue of patients with lung brosis and appears to be involved in regulating alveolar epithelial regeneration [9,10]. A large multicenter cohort study also found OPG to be a biomarker of progressive brosing interstitial lung disease [11].…”

“…However, we have additionally shown that OPG is produced and secreted by lung broblasts under the in uence of the key pro brotic mediator transforming growth factor beta 1 (TGFβ1) [14]. Interestingly, our recent studies indicate that through its capturing of RANKL it can also inhibit alveolar epithelial repair [9,10]. However, it is unknown if other brosis-associated cytokines like interleukin-13 (IL13) can induce OPG expression in lung tissue and how OPG secretion is affected by treatment with the two anti brotic drugs currently on the market.…”