R-spondin 2 is Upregulated in Idiopathic Pulmonary Fibrosis and Affects Fibroblasts Behavior.

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Abstract

Idiopathic pulmonary fibrosis (IPF) is characterized by the expansion of the myofibroblasts population, excessive extracellular matrix accumulation, and destruction of the lung parenchyma. The R-spondins family (RSPO) comprises a group of proteins essential for development. From them, RSPO2 is expressed primarily in the lungs and its mutations cause severe defects in the respiratory tract. Interestingly, RSPO2 participates in the canonical WNT 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 LGR6 were upregulated in IPF lungs where they localized primarily in fibroblasts and epithelial cells. Stimulation of IPF and normal lung fibroblasts with recombinant hRSPO2 resulted in the deregulation of numerous genes although the transcriptional response was essentially distinct. In IPF fibroblasts, RSPO2 stimulation induced the up- or down-regulation of several genes involved in the WNT pathway (mainly from non-canonical signaling). In both, normal and IPF fibroblasts RSPO2 modifies the expression of genes implicated in several pathways including cell cycle and apoptosis. According with the 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 (MMP)-1. Silencing RSPO2 with short hairpin RNA induced the opposite effects. Our findings demonstrate by the first time that RSPO2 is up-regulated in IPF where it appears to have an antifibrotic role.

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