RANKL Dependent Differentiation of Pulmonary Osteoclast-Like Cells in Silica-Induced Pulmonary Fibrosis

Tanaka, Yuya; Shaver, Ciara M.; Brown, Kevin K.; Perkins, Charles; Pistick, L.B.; McKnight, Christopher; Wu, Huixing; Kopras, E.J.-A.; McCormack, Francis X.

doi:10.1164/ajrccm-conference.2020.201.1_meetingabstracts.a2253

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“…RANKL levels have been found to be elevated in patients with lung diseases such as COPD (4) and cystic fibrosis (5), as well as in BAL fluid and in ATII cells of mice with silica-induced fibrosis (6). The cellular origin of this RANKL production is not completely clear yet, but it is at least produced by lung fibroblasts as we have shown in our previous study (3, 15).…”

Section: Discussionmentioning

confidence: 99%

“…It is best known for its action as a stimulator of bone tissue degradation and has an important role in bone extracellular matrix regulation (1, 2). RANKL is also found in lung tissue (3) and higher levels have been reported in lung diseases like chronic obstructive pulmonary disease (COPD) (4), cystic fibrosis (5) and silica-induced pulmonary fibrosis (6). These higher levels of RANKL may explain the association of these diseases with osteoporosis (4, 5, 7).…”

Section: Introductionmentioning

confidence: 99%

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

Habibie,

Song,

Boorsma

et al. 2023

Preprint

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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.

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