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Published on: January 27, 2023
RLX-2 ameliorates post-traumatic joint contracture by inhibiting the cGAS-STING signaling pathway
Jian-Jun Chen1, Quan-Bing Zhang2, Yan Wang2
1Department of Rehabilitation Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230601, China; Department of Rehabilitation Medicine, Hefei First People's Hospital, Hefei, Anhui 230001, China.
Objectives:
Post-traumatic joint contracture (PTJC) is a debilitating fibrotic disorder whose underlying molecular drivers, particularly the involvement of cellular senescence, remain poorly elucidated. This study aimed to evaluate the therapeutic potential of Relaxin-2 (RLX-2) in attenuating knee joint fibrosis and to explore its regulatory effects on the cGAS-STING signaling axis.
Methods:
In vitro fibrotic phenotypes were recapitulated using TGF-β1-stimulated rat synovial fibroblasts. An in vivo PTJC model was established via surgical trauma combined with internal fixation-induced immobilization in rats. The anti-fibrotic and anti-senescent properties of RLX-2 were characterized by quantifying markers such as Collagen I, α-SMA, p16, and p53. Transcriptomic profiling via RNA-sequencing was employed to identify potential signaling hubs. The mechanistic involvement of the cGAS-STING pathway was further interrogated using the pharmacological inhibitor H-151 in both experimental settings.
Results:
In vitro, RLX-2 treatment exerted a concentration-dependent inhibitory effect on TGF-β1-induced fibrogenic transition and cellular senescence. In the rat model, intra-articular administration of RLX-2 resulted in a significant reduction in synovial hyperplasia and extracellular matrix deposition. These phenotypic improvements were associated with the downregulation of senescence markers in the synovium. Mechanistically, RNA-seq analysis pointed toward the cGAS-STING pathway as a primary target of RLX-2. RLX-2 administration was associated with decreased phosphorylation of STING and its downstream effector TBK1. Notably, pharmacological blockade of STING by H-151 partially phenocopied the protective effects of RLX-2, suggesting a coordinated regulation of fibrosis and senescence.
Conclusion:
Our findings demonstrate that RLX-2 attenuates post-traumatic knee joint fibrosis in rats, a process associated with the modulation of the cGAS-STING-senescence axis. These results suggest that targeting the cGAS-STING pathway may represent a viable strategy for managing PTJC, with RLX-2 serving as a promising pharmacological candidate for further clinical investigation.
Insights
Relaxin-2 (RLX-2) reduces knee joint fibrosis and cellular senescence in rats by modulating the cGAS-STING pathway. This suggests RLX-2 is a promising treatment for post-traumatic joint contracture (PTJC).
Area of Science:
- Fibrosis research
- Cellular senescence
- Molecular signaling pathways
Background:
- Post-traumatic joint contracture (PTJC) is a fibrotic disorder with poorly understood molecular drivers.
- Cellular senescence is implicated in PTJC pathogenesis.
- Effective therapeutic strategies for PTJC are limited.
Purpose of the Study:
- To evaluate Relaxin-2 (RLX-2) as a treatment for knee joint fibrosis.
- To investigate RLX-2's effect on cellular senescence in PTJC.
- To explore RLX-2's regulatory role in the cGAS-STING signaling axis.
Main Methods:
- Established in vitro and in vivo models of PTJC.
- Assessed anti-fibrotic and anti-senescent effects of RLX-2 using molecular markers.
- Utilized RNA-sequencing for transcriptomic profiling.
- Investigated the cGAS-STING pathway using a pharmacological inhibitor (H-151).
Main Results:
- RLX-2 inhibited TGF-β1-induced fibrosis and senescence in vitro.
- Intra-articular RLX-2 reduced synovial hyperplasia and extracellular matrix deposition in vivo.
- RLX-2 downregulated senescence markers and modulated the cGAS-STING pathway.
- STING inhibition partially mimicked RLX-2's protective effects.
Conclusions:
- RLX-2 attenuates PTJC in rats by modulating the cGAS-STING-senescence axis.
- Targeting the cGAS-STING pathway offers a potential strategy for PTJC management.
- RLX-2 is a promising candidate for further clinical investigation in PTJC.