Runt-related transcription factor 2 in pulmonary fibrosis

Mümmler, Carlo (2019): Runt-related transcription factor 2 in pulmonary fibrosis. Dissertation, LMU München: Faculty of Medicine

Abstract

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with unknown etiology and limited therapeutic options. IPF is characterized by epithelial cell injury, impaired cellular crosstalk between epithelial cells and fibroblasts, and the formation of fibroblast foci with increased extracellular matrix (ECM) deposition. In rare cases, this can even lead to pulmonary ossification. We investigated the cell-specific expression and pathophysiologic role of runt-related transcription factor (RUNX) 2, a master regulator of bone development linked to profibrotic signaling. RUNX2 expression was upregulated in experimental bleomycin-induced lung fibrosis (BLEO) as well as in lung homogenates from IPF patients. RUNX2 levels correlated with disease severity as measured by decreased diffusing capacity of the lung for carbon monoxide (DLCO) or increased levels of the IPF biomarkers MMP7 and SPP1. We observed nuclear RUNX2 expression in proSPC-positive hyperplastic epithelial cells in IPF, demonstrated an increase of a proSPC-positive/RUNX2-positive epithelial cell population in IPF and BLEO and showed that RUNX2 expression was increased in alveolar epithelial type (AT) II cells isolated from bleomycin-treated mice. Interestingly, the increase in αSMA-positive myofibroblasts in pulmonary fibrosis was mainly due to an increase in a RUNX2-negative cell population. Further evidence demonstrated that primary human lung fibroblasts (phLF) isolated from IPF tissue displayed reduced levels of RUNX2. Functionally, siRNA-mediated RUNX2 knockdown decreased expression of S100A4 and CCND1 in murine ATII cells and impaired the migration of A549 cells. In phLF, RUNX2 knockdown led to an induction of mesenchymal markers ACTA2, TNC and COL1A1 while CCND1 and S100A4 were decreased. In summary, this study suggests that regulation of RUNX2 expression contributes to fibrotic processes in the lung. In alveolar epithelial cells, upregulation of RUNX2 induced cell proliferation and migration whereas the downregulation of RUNX2 in fibroblasts contributed to the increased ECM deposition. We conclude, that cell-specific targeting of RUNX2 may represent a novel therapeutic approach for IPF.

• Item Type: Theses (Dissertation, LMU Munich)
• Keywords: IPF, RUNX2, alveolar epithelial cells, fibroblast
• Subjects: 600 Technology, Medicine; 600 Technology, Medicine > 610 Medical sciences and medicine
• Faculties: Faculty of Medicine
• Language: English
• Date of oral examination: 10. January 2019
• 1. Referee: Königshoff, Melanie
• Signature of the printed copy: 0700/UMD 18350