eCM (Eur Cell Mater / e Cells & Materials) eCM Open Access Scientific Journal
 ISSN:1473-2262         NLM:100973416 (link)         DOI:10.22203/eCM

2024   Volume No 47 – pages 59-72

Title: Nicorandil mitigates arthrogenic contracture induced by knee joint extension immobilization in rats: interference with RhoA/ROCK signaling and TGF-β1/Smad pathway

Authors:  XM Li, K Wang, M Liu, QB Zhang, Y Zhou

Address: Department of Rehabilitation Medicine, The Second Affiliated Hospital of Anhui Medical University, No.678 Furong Road, Economic and Technological Development Zone, Hefei 230601, China

E-mail: zhouyunanhui at

Abstract: Objective: Prolonged immobilization often results in myogenic and arthrogenic contractures, with capsular fibrosis being the critical aspect of the latter. This study aimed to determine whether nicorandil can mitigate joint contracture and fibrosis by inhibiting the RhoA/ROCK signaling pathway, thereby affecting the TGF-β1/Smad signaling pathway. Materials and Methods: This study used a rat model of knee extensor joint immobilization to assess the impact of nicorandil on arthrogenic contracture and joint capsule fibrosis. Sixty Sprague–Dawley rats were divided into control, immobilization, and nicorandil treatment groups with varying durations of immobilization. The extent of arthrogenic contracture was assessed using joint mobility metrics, while joint capsule fibrosis was quantified using Masson staining, α-SMA immunohistochemistry, and H&E staining. The protein expression levels of the TGF-β1/Smad and RhoA/ROCK signaling pathways were analyzed by western blotting. Additionally, lysophosphatidic acid (LPA), a specific ROCK activator, was used to further investigate the involvement of RhoA/ROCK signaling in TGF-β1/Smad pathway modulation. Results: This study revealed a positive correlation between the duration of immobilization and the severity of arthrogenic contracture, joint capsule fibrosis, and inflammatory infiltration. Nicorandil administration effectively reduced these immobilization-induced changes and concurrently inhibited the activation of TGF-β1/Smad and RhoA/ROCK signaling pathways. Application of LPA counteracted the inhibitory effects of nicorandil on these pathways. Conclusion: Nicorandil significantly alleviated arthrogenic contracture and joint capsule fibrosis resulting from knee extension immobilization. The underlying mechanism appears to involve inhibition of the TGF-β1/Smad signaling pathway, mediated by RhoA/ROCK signaling pathway suppression.

Keywords: Nicorandil, arthrogenic contracture, fibrosis, TGF-β1/Smad signaling pathway, RhoA/ROCK signaling pathway.

Publication date: March 15th 2024

Copyright policy: © 2024 The Author(s). Published by Forum Multimedia Publishing, LLC. This article is distributed in accordance with Creative Commons Attribution Licence (

Article download: Pages 59-72 (PDF file)

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