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Am J Respir Cell Mol Biol. 2018 Jul;59(1):65-76. doi: 10.1165/rcmb.2017-0115OC.

R-Spondin-2 Is Upregulated in Idiopathic Pulmonary Fibrosis and Affects Fibroblast Behavior.

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1 Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas (INER), Mexico City, Mexico.
2 Cátedra Consejo Nacional de Ciencia y Tecnología (CONACyT)-INER, Mexico City, Mexico.
3 Facultad de Ciencias, Universidad Nacional Autónoma de México, Mexico City, Mexico; and.
4 Instituto Nacional de Medicina Genómica, Mexico City, Mexico.


Idiopathic pulmonary fibrosis (IPF) is characterized by the expansion of the myofibroblast population, excessive extracellular matrix accumulation, and destruction of the lung parenchyma. The R-spondin family (RSPO) comprises a group of proteins essential for development. Among them, RSPO2 is expressed primarily in the lungs, and its mutations cause severe defects in the respiratory tract. Interestingly, RSPO2 participates in the canonical Wingless/int1 pathway, a critical route in the pathogenesis of IPF. Thus, the aim of this study was to examine the expression and putative role of RSPO2 in this disease. We found that RSPO2 and its receptor leucine-rich G protein-coupled receptor 6 were upregulated in IPF lungs, where they localized primarily in fibroblasts and epithelial cells. Stimulation of IPF and normal lung fibroblasts with recombinant human RSPO2 resulted in the deregulation of numerous genes, although the transcriptional response was essentially distinct. In IPF fibroblasts, RSPO2 stimulation induced the up- or downregulation of several genes involved in the Wingless/int1 pathway (mainly from noncanonical signaling). In both normal and IPF fibroblasts, RSPO2 modifies the expression of genes implicated in several pathways, including the cell cycle and apoptosis. In accordance with gene expression, the stimulation of normal and IPF fibroblasts with RSPO2 significantly reduced cell proliferation and induced cell death. RSPO2 also inhibited collagen production and increased the expression of matrix metalloproteinase 1. Silencing RSPO2 with shRNA induced the opposite effects. Our findings demonstrate, for the first time to our knowledge, that RSPO2 is upregulated in IPF, where it appears to have an antifibrotic role.


R-spondin; Wnt pathway; cell cycle; fibroblasts; idiopathic pulmonary fibrosis

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