Premium
R‐Spondin2 is upregulated in idiopathic pulmonary fibrosis and affects fibroblasts behavior
Author(s) -
Munguia Adrian,
Becerril Carina,
Mendoza Criselda,
Balderas Yalbi,
Ramirez Remedios,
Melendez Jorge,
Pardo Annie,
Selman Moises
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.50.7
Subject(s) - wnt signaling pathway , biology , cancer research , axin2 , pathology , microbiology and biotechnology , signal transduction , medicine
Backgroud Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and lethal lung disorder of unknown etiology characterized by fibroblast activation, excessive extracellular matrix accumulation and the subsequent destruction of the lung parenchyma. The R‐spondins family (RSPO) represents a recently described group of proteins with essential activities in development. RSPO2 is expressed primarily in the lungs and mutations of this protein cause severe defects in the respiratory tract. Three proteins of the G protein coupled family (LGR4, LGR5 and LGR6) have been identified as possible receptors. RSPO2 enhances the canonical Wnt signaling (a pathway involved in IPF) resulting in activation of b‐catenin. Aim To determine the role of RSPO2 in IPF. Methods The expression of RSPO2 and LGR6 was explored by qPCR in IPF lungs and fibroblasts. Cell source was analyzed by immunohistochemistry. The effect of RSPO2 on lung fibroblasts proliferation was evaluated with WST1 and on gene expression by RNAseq. The effect of RSPO2 on fibroblasts and epithelial cell apoptosis was examined by flow cytometry. Results RSPO2 and LGR6 were significantly increased (>100‐fold) in IPF compared with normal lungs. Both molecules were localized primarily in fibroblasts and epithelial cells. RSPO2 gene expression was also increased in fibroblasts derived from IPF lungs (2 −DCT 2.59 −5 ±3.6 −6 vs 1.39 −5 ±1.35 −6 ). In vitro, RSPO2 modified the expression of 3116 genes in IPF and 795 in normal fibroblasts. Several pathways were revealed including apoptosis, cell cycle, Wnt pathway, and extracellular matrix metabolism. Treatment of fibroblasts with RSPO2 reduced cell proliferation and induced apoptosis in both normal and IPF fibroblasts. No effect was observed in epithelial cell apoptosis. Conclusions Our findings demonstrate that RSPO2 and its receptor LGR6 are upregulated in IPF lungs, primarily in fibroblasts and epithelial cells, although the exact role of this axis in the pathogenesis of this disease remains uncertain. Support or Funding Information Posgrado en Ciencias Biologicas, UNAM