期刊
MOLECULAR GENETICS & GENOMIC MEDICINE
卷 8, 期 4, 页码 -出版社
WILEY
DOI: 10.1002/mgg3.1194
关键词
alternative splicing; fibrosis; relaxin; RXFP1
资金
- Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease
- National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH [1R21AR076024-01, R01 HL126990, 5P50AR060780-08]
Background 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. Methods 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. Results 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. Conclusions 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.
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