Expression of RXFP1 Is Decreased in Idiopathic Pulmonary Fibrosis. Implications for Relaxin-based Therapies

Abstract

Rationale: Relaxin is a hormone that has been considered as a potential therapy for patients with fibrotic diseases.Objectives: To gauge the potential efficacy of relaxin-based therapies in idiopathic pulmonary fibrosis (IPF), we studied gene expression for relaxin/insulin-like family peptide receptor 1 (RXFP1) in IPF lungs and controls.Methods: We analyzed gene expression data obtained from the Lung Tissue Research Consortium and correlated RXFP1 gene expression data with cross-sectional clinical and demographic data. We also employed ex vivo donor and IPF lung fibroblasts to test RXFP1 expression in vitro. We tested CGEN25009, a relaxin-like peptide, in lung fibroblasts and in bleomycin injury. Measurements and Main Results:We found that RXFP1 is significantly decreased in IPF. In patients with IPF, the magnitude of RXFP1 gene expression correlated directly with diffusing capacity of the lung for carbon monoxide (P , 0.0001). Significantly less RXFP1 was detected in vitro in IPF fibroblasts than in donor controls. Transforming growth factor-b decreased RXFP1 in both donor and IPF lung fibroblasts. CGEN25009 was effective at decreasing bleomycin-induced, acid-soluble collagen deposition in vivo. The relaxin-like actions of CGEN25009 were abrogated by RXFP1 silencing in vitro, and, in comparison with donor lung fibroblasts, IPF lung fibroblasts exhibited decreased sensitivity to the relaxin-like effects of CGEN25009.Conclusions: IPF is characterized by the loss of RXFP1 expression. RXFP1 expression is directly associated with pulmonary function in patients with IPF. The relaxin-like effects of CGEN25009 in vitro are dependent on expression of RXFP1. Our data suggest that patients with IPF with the highest RXFP1 expression would be predicted to be most sensitive to relaxin-based therapies.Keywords: relaxin; pulmonary fibrosis; transforming growth factor-b; RXFP1 At a Glance CommentaryScientific Knowledge on the Subject: Relaxin and relaxinbased therapies have been considered as potential therapies for pulmonary fibrosis.What This Study Adds to the Field: We found that expression of the relaxin receptor, RXFP1, is decreased in idiopathic pulmonary fibrosis and is associated with impaired pulmonary function. Understanding how RXFP1 is regulated is critical to the success of relaxin-based therapies in idiopathic pulmonary fibrosis.

Loss of Twist1 in the Mesenchymal Compartment Promotes Increased Fibrosis in Experimental Lung Injury by Enhanced Expression of CXCL12

“…To explore this question, we analyzed data from the LGRC as described in Materials and Methods. The LGRC cohort(47) is described in Table 2. These data combine gene expression analysis from whole lung homogenates with cross-sectional clinical data.…”

RXFP1 expression is regulated by miR-144-3p in Fibroblasts from Patients with Idiopathic Pulmonary Fibrosis

“…These include the seminal observation that mice genetically engineered to lose expression of the hormone relaxin (encoded in humans by RLN2) developed a progressive, age-related multi-organ fibrosis that was reversible with exogenous relaxin (4)(5)(6). In further support of the importance of this pathway, we have shown that gene expression levels for the relaxin receptor, RXFP1, in IPF is directly associated with pulmonary function (7). Furthermore, RXFP1 protein expression was dramatically decreased in both IPF lungs and IPF lung fibroblasts compared to donor controls.…”

Simultaneously Targeting Myofibroblast Contractility and Extracellular Matrix Cross-Linking as a Therapeutic Concept in Airway Fibrosis

“…Tan et al found that RXFP1 is significantly decreased in the lungs of idiopathic pulmonary fibrosis (IPF) patients, and suggested that progression of IPF may be associated with sequential decreases of RXFP1 expression (21). In our study, because relaxin’s positive effects were dampened by a stiff microenvironment in vitro , we speculated that the expression of RXFP1 is modulated by a progressive increase in ECM stiffness.…”

“…However, as stated above, phase 2 and 3 trials of relaxin did not demonstrate any efficacy in the treatment of fibrosis in systemic sclerosis (8). It has been shown that RXFP1 level is decreased in lungs of IPF patients (21). We found that fibroblasts that were plated on stiff matrices had significant lower RXFP1 expressions than those plated on soft matrices.…”