Relaxin and extracellular matrix remodeling: Mechanisms and signaling pathways

Abstract

Fibrosis is associated with accumulation of excess fibrillar collagen, leading to tissue dysfunction. Numerous processes, including inflammation, myofibroblast activation, and endothelial-tomesenchymal transition, play a role in the establishment and progression of fibrosis. Relaxin is a peptide hormone with well-known antifibrotic properties that result from its action on numerous cellular targets to reduce fibrosis. Relaxin activates multiple signal transduction pathways as a mechanism to suppress inflammation and myofibroblast activation in fibrosis. In this review, the general mechanisms underlying fibrotic diseases are described, along with the current state of knowledge regarding cellular targets of relaxin. Finally, an overview is presented summarizing the signaling pathways activated by relaxin and other relaxin family peptide receptor agonists to suppress fibrosis.

Relaxin and fibrosis: Emerging targets, challenges, and future directions

“…Furthermore, it can reduce established scarring by promoting the degradation of aberrant extracellular matrix components. Following on from the review that describes the mechanisms and signaling pathways associated with the extracellular matrix remodeling effects of serelaxin (Ng et al, 2019), this review focuses on newly identified tissue targets of serelaxin therapy in fibrosis, and the limitations associated with (se)relaxin research.…”

Potential Molecular Mechanisms of Plantain in the Treatment of Gout and Hyperuricemia Based on Network Pharmacology

“…Figure 9 shows the results of relaxin signaling pathway analysis. In terms of anti-inflammation, relaxin can inhibit the adhesion of neutrophils to endothelial cells and the infiltration of macrophages, can inhibit the activity of NLRP3 inflammasome and NF- κ B signaling pathway to reduce the inflammatory reaction, and can reduce the levels of cytokines, such as IL-1 β , IL-6, and TNF- α [ 57 ]. For example, relaxin can reduce cardiac inflammatory response by reducing the inflammation mediated by IL-1 β , IL-6, and NLRP3 [ 58 , 59 ] and also can inhibit vascular inflammation by inhibiting the expression of TNF- α and chemokine C-C motif ligand 2 (CCL2) [ 60 ].…”

“…Studies have found that relaxin and estrogen can reduce TNF- α and vascular endothelial growth factor by increasing the expression of relaxin family peptide receptor (RXFP1) gene and can increase the expression of anti-inflammatory cytokine IL-10 to improve the symptoms of adjuvant-induced RA in rats [ 61 – 63 ]. In terms of antifibrosis effect, relaxin can inhibit Smad2 phosphorylation level and fibrosis mediator transforming growth factor- β 1(TGF- β 1) and promote the expression of MMP-1/2/9/13 by activating RXFP1, so as to reduce the production and deposition of collagen to achieve the antifibrosis effect [ 57 ]. Previous studies have found that TGF- β 1 expression was increased in synovium of patients with acute gouty arthritis and in the fibrotic kidney of patients with hyperuricemia [ 64 – 66 ].…”

Adult fibroblasts retain organ-specific transcriptomic identity

“…The top pathways up-regulated by Tbx20KD involved IL-17 and relaxin signaling, as well as transcription misregulation in cancer. IL17 has been shown to regulate the fibrotic response in pro-inflammatory conditions such as psoriasis and pulmonary/liver fibrosis [46][47][48][49], while relaxin has a well-established role in suppressing myofibroblast activation and ECM remodeling [50][51][52].…”