Relaxin as a treatment for musculoskeletal fibrosis: What we know and future directions

Abstract

Fibrotic changes in musculoskeletal diseases arise from the abnormal buildup of fibrotic tissue around the joints, leading to limited mobility, compromised joint function, and diminished quality of life. Relaxin (RLX) attenuates fibrosis by accelerating collagen degradation and inhibiting excessive extracellular matrix (ECM) production. Further, RLX disrupts myofibroblast activation by modulating the TGF-β/Smads signaling pathways, which reduces connective tissue fibrosis. However, the mechanisms and effects of RLX in musculoskeletal pathologies are emerging as increasing research focuses on relaxin's impact on skin, ligaments, tendons, cartilage, joint capsules, connective tissues, and muscles. This review delineates the actions of relaxin within the musculoskeletal system and the challenges to its clinical application. Relaxin shows significant potential in both in vivo and in vitro studies for broadly managing musculoskeletal fibrosis; however, challenges such as short biological half-life and sex-specific responses may pose hurdles for clinical use.

Keywords: Joint; Musculoskseletal fibrosis; Range of motion; Relaxin; Treatment.

Figure 1.

Common and distinct mechanisms in different stages of fibrotic tissue remodelling (adapted form [1]). This summary examines the overlapping and unique fibrotic processes implicated in the onset and advancement of fibrotic disorders. It underscores the presence of distinct mechanisms driving early-stage tissue fibrosis, while later stages are characterized by predominantly shared fibrotic pathways. Specific triggers linked to particular diseases and anatomical locations prompt the infiltration and activation of immune cells, along with the polarization of T helper 2 (TH2) cells and M2 macrophages, leading to the release of various pro-fibrotic cytokines. This pro-fibrotic environment triggers the activation of resident fibroblasts and prompts the transformation of diverse cell types—including epithelial cells, pericytes, endothelial cells, and bone marrow-derived fibrocytes—into myofibroblasts. Ongoing tissue remodeling establishes self-perpetuating activation cycles, such as increased tissue rigidity or hypoxia, which sustain the activated state of myofibroblasts in fibrotic conditions. Additionally, key terms are abbreviated as follows: 5-HT (5-hydroxytryptamine, serotonin), 5-HT2 (5-HT receptor 2), ECM (extracellular matrix), ILC1 (group 1 innate lymphoid cell), PDGF (platelet-derived growth factor), and TGFβ (transforming growth factor-β).

Figure 2.

A schematic diagram of the primary signaling transduction mechanisms by RLX/RXFP1 in stromal cells, involved in RLX antifibrotic effects (adapted from [2]). A detailed schematic diagram illustrating the primary signaling transduction pathways activated by Relaxin (RLX) binding to its receptor, RXFP1, within stromal cells, and their role in mediating RLX’s antifibrotic effects. The diagram should depict RLX binding to the extracellular domain of RXFP1, initiating a sequence of intracellular events. These include the activation of multiple downstream signaling pathways such as cAMP/PKA, PI3K/Akt, and Notch-1 which inhibits the TGFb-1 receptor activation and its consequences fibrotic effects.