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Abstract <p>This study investigates the potential of nintedanib, a tyrosine kinase inhibitor with antifibrotic and anti-inflammatory properties, to mitigate post-traumatic joint contracture (PTJC) in a rat model. Given the lack of effective pharmacological treatments for this debilitating condition, this study aims to address the unmet need for non-surgical interventions by targeting the underlying fibrotic and inflammatory processes. A total of 26 male Sprague–Dawley rats were subjected to standardized knee trauma and immobilization for 2&#xa0;weeks. Rats were randomized into two groups: a nintedanib treatment group (5&#xa0;mg/kg taken twice daily, <i>n</i> = 13) and a placebo group (<i>n</i> = 13). Joint mobility was evaluated biomechanically by measuring the contracture angle (CA) and resistance to extension. Posterior joint capsule tissues were analyzed histologically and via qPCR for profibrotic gene expression, including <i>α-Sma</i>, <i>Il-6</i>, <i>Tgf-β1</i>, <i>Nf-κb</i>, and <i>Ctgf</i>. Nintedanib treatment significantly reduced CA compared to placebo (68.1° ± 12.6° vs. 84.8° ± 11.1°, <i>p</i> &lt; 0.01), indicating improved joint mobility. Knee extension in the nintedanib-treated rats required less force, particularly at lower extension angles (<i>p</i> &lt; 0.05). Molecular analysis showed a marked reduction in <i>α-Sma</i> expression, a myofibroblast marker, in the nintedanib group compared to placebo (11-fold decrease, <i>p</i> &lt; 0.05). Histological examinations revealed relatively fewer myofibroblasts in the posterior joint capsule of rats treated with nintedanib. Nintedanib effectively mitigates fibrosis and inflammation in a rat model of PTJC, enhancing joint mobility and reducing profibrotic gene expression. These findings support further exploration of nintedanib as a pharmacological therapy for PTJC in clinical settings.</p> Key messages <p><UnorderedList Mark="Bullet"> <ItemContent> <p>Nintedanib is a promising candidate for the prevention of post-traumatic joint contracture.</p> </ItemContent> <ItemContent> <p>Oral administration of nintedanib (5&#xa0;mg twice daily) over a period of 2&#xa0;weeks improves joint mobility in post-traumatic joint contracture (PTJC).</p> </ItemContent> <ItemContent> <p>Nintedanib reduces the relative number of myofibroblasts.</p> </ItemContent> <ItemContent> <p>A significant reduction in <i>α-SMA</i> expression levels under the influence of nintedanib indicates a slowed transition of fibroblasts to myofibroblasts.</p> </ItemContent> </UnorderedList></p>

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Nintedanib reduces severity of post-traumatic joint contracture by modulating fibrosis and inflammation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月25日

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  • Erik Wegner,
  • Dennis Warnke,
  • Victoria Buschmann,
  • Benedikt Hild,
  • Berenika Mais,
  • Ulrike Ritz,
  • Austin Harper,
  • Erol Gercek,
  • Philipp Drees,
  • Andreas Baranowski

摘要

Abstract

This study investigates the potential of nintedanib, a tyrosine kinase inhibitor with antifibrotic and anti-inflammatory properties, to mitigate post-traumatic joint contracture (PTJC) in a rat model. Given the lack of effective pharmacological treatments for this debilitating condition, this study aims to address the unmet need for non-surgical interventions by targeting the underlying fibrotic and inflammatory processes. A total of 26 male Sprague–Dawley rats were subjected to standardized knee trauma and immobilization for 2 weeks. Rats were randomized into two groups: a nintedanib treatment group (5 mg/kg taken twice daily, n = 13) and a placebo group (n = 13). Joint mobility was evaluated biomechanically by measuring the contracture angle (CA) and resistance to extension. Posterior joint capsule tissues were analyzed histologically and via qPCR for profibrotic gene expression, including α-Sma, Il-6, Tgf-β1, Nf-κb, and Ctgf. Nintedanib treatment significantly reduced CA compared to placebo (68.1° ± 12.6° vs. 84.8° ± 11.1°, p < 0.01), indicating improved joint mobility. Knee extension in the nintedanib-treated rats required less force, particularly at lower extension angles (p < 0.05). Molecular analysis showed a marked reduction in α-Sma expression, a myofibroblast marker, in the nintedanib group compared to placebo (11-fold decrease, p < 0.05). Histological examinations revealed relatively fewer myofibroblasts in the posterior joint capsule of rats treated with nintedanib. Nintedanib effectively mitigates fibrosis and inflammation in a rat model of PTJC, enhancing joint mobility and reducing profibrotic gene expression. These findings support further exploration of nintedanib as a pharmacological therapy for PTJC in clinical settings.

Key messages

Nintedanib is a promising candidate for the prevention of post-traumatic joint contracture.

Oral administration of nintedanib (5 mg twice daily) over a period of 2 weeks improves joint mobility in post-traumatic joint contracture (PTJC).

Nintedanib reduces the relative number of myofibroblasts.

A significant reduction in α-SMA expression levels under the influence of nintedanib indicates a slowed transition of fibroblasts to myofibroblasts.