Division of Pulmonary, Allergy and Critical Care Medicine and the Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease, University of Pittsburgh, Pittsburgh, PA, USA.
Institute of Allied Health Sciences, National Cheng Kung University, Tainan, Taiwan.
Mol Genet Genomic Med. 2020 Apr;8(4):e1194. doi: 10.1002/mgg3.1194. Epub 2020 Feb 26.
Relaxin/relaxin family peptide receptor 1 (RXFP1) signaling is important for both normal physiology and disease. Strong preclinical evidence supports relaxin as a potent antifibrotic molecule. However, relaxin-based therapy failed in clinical trial in patients with systemic sclerosis. We and others have discovered that aberrant expression of RXFP1 may contribute to the abnormal relaxin/RXFP1 signaling in different diseases. Reduced RXFP1 expression and alternative splicing transcripts with potential functional consequences have been observed in fibrotic tissues. A relative decrease in RXFP1 expression in fibrotic tissues-specifically lung and skin-may explain a potential insensitivity to relaxin. In addition, receptor dimerization also plays important roles in relaxin/RXFP1 signaling.
This review describes the tissue specific expression, characteristics of the splicing variants, and homo/heterodimerization of RXFP1 in both normal physiological function and human diseases. We discuss the potential implications of these molecular features for developing therapeutics to restore relaxin/RXFP1 signaling and to harness relaxin's potential antifibrotic effects.
Relaxin/RXFP1 signaling is important in both normal physiology and in human diseases. Reduced expression of RXFP1 in fibrotic lung and skin tissues surrenders both relaxin/RXFP1 signaling and their responsiveness to exogenous relaxin treatments. Alternative splicing and receptor dimerization are also important in regulating relaxin/RXFP1 signaling.
Understanding the molecular mechanisms that drive aberrant expression of RXFP1 in disease and the functional roles of alternative splicing and receptor dimerization will provide insight into therapeutic targets that may restore the relaxin responsiveness of fibrotic tissues.
松弛素/松弛素家族肽受体 1（RXFP1）信号对于正常生理和疾病都很重要。强有力的临床前证据支持松弛素作为一种有效的抗纤维化分子。然而，基于松弛素的治疗在系统性硬化症患者的临床试验中失败了。我们和其他人发现，RXFP1 的异常表达可能导致不同疾病中松弛素/RXFP1 信号的异常。在纤维化组织中观察到 RXFP1 表达减少和具有潜在功能后果的剪接变体。纤维化组织（特别是肺和皮肤）中 RXFP1 表达的相对减少可能解释了对松弛素的潜在不敏感性。此外，受体二聚化在松弛素/RXFP1 信号中也起着重要作用。
本综述描述了 RXFP1 在正常生理功能和人类疾病中的组织特异性表达、剪接变体的特征以及同源/异源二聚化。我们讨论了这些分子特征对开发恢复松弛素/RXFP1 信号和利用松弛素潜在抗纤维化作用的治疗方法的潜在影响。
松弛素/RXFP1 信号在正常生理和人类疾病中都很重要。纤维化肺和皮肤组织中 RXFP1 的表达减少，使松弛素/RXFP1 信号及其对外源松弛素治疗的反应性都丧失。剪接和受体二聚化在调节松弛素/RXFP1 信号中也很重要。
了解导致疾病中 RXFP1 异常表达的分子机制以及剪接变体和受体二聚化的功能作用，将为恢复纤维化组织对松弛素的反应性提供治疗靶点的见解。
