Department of Orthopaedics and Traumatology, Biomatics Group, University Medical Center of the Johannes Gutenberg University, Mainz 55131, Germany.
Department of Diagnostic and Interventional Radiology, University Medical Center of the Johannes Gutenberg University, Mainz 55131, Germany; Mainz Research School of Translational Biomedicine, University Medical Center of the Johannes Gutenberg University, Mainz 55131, Germany.
Biomed Pharmacother. 2023 Oct;166:115291. doi: 10.1016/j.biopha.2023.115291. Epub 2023 Aug 7.
Post-traumatic joint stiffness (PTJS) is accompanied by a multidimensional disturbance of joint architecture. Pharmacological approaches represent promising alternatives as the traumatic nature of current therapeutic standards may lead to PTJS' progression. Losartan is an auspicious candidate, as it has demonstrated an antifibrotic effect in other organs. Forty-eight Sprague Dawley rats were randomized into equally sized losartan or control groups. After a standardized knee trauma, the joint was immobilized for either 2 weeks (n = 16), 4 weeks (n = 16) or 4 weeks with re-mobilization for an additional 4 weeks (n = 16). Pharmacotherapy with losartan or placebo (30 mg/kg/day) was initiated on the day of trauma and continued for the entire course. Joint contracture was measured alongside histological and molecular biological assessments. There were no significant biomechanical changes in joint contracture over time, comparing short-term (2 weeks) with long-term losartan therapy (4 weeks). However, comparing the formation of PTJS with that of the control, there was a trend toward improvement of joint mobility of 10.5° (p 0.09) under the influence of losartan. During the re-mobilization phase, no significant effect of losartan on range of motion (ROM) was demonstrated. At a cellular level, losartan significantly reduced myofibroblast counts by up to 72 % (4 weeks, p ≤ 0.001) without effecting the capsular configuration. Differences in expression levels of profibrotic factors (TGF-β, CTGF, Il-6) were most pronounced at week 4. The antifibrotic properties of losartan are not prominent enough to completely prevent the development of PTJS after severe joint injury.
创伤后关节僵硬（PTJS）伴随着关节结构的多维障碍。药理学方法代表了有希望的替代方案，因为当前治疗标准的创伤性质可能导致 PTJS 的进展。氯沙坦是一个有前途的候选者，因为它在其他器官中表现出抗纤维化作用。48 只 Sprague Dawley 大鼠被随机分为氯沙坦或对照组，每组 16 只。在标准化膝关节创伤后，关节固定 2 周（n=16）、4 周（n=16）或 4 周后再固定 4 周（n=16）。创伤当天开始进行氯沙坦或安慰剂（30mg/kg/天）的药物治疗，并持续整个疗程。同时进行关节挛缩测量以及组织学和分子生物学评估。在短时间（2 周）与长时间（4 周）氯沙坦治疗的比较中，关节挛缩没有随时间发生显著的生物力学变化。然而，与对照组相比，氯沙坦对关节活动度的改善趋势为 10.5°（p=0.09）。在再活动阶段，氯沙坦对关节活动度（ROM）没有显著影响。在细胞水平上，氯沙坦可将肌成纤维细胞计数减少多达 72%（4 周，p≤0.001），而不影响囊配置。在第 4 周时，纤维原性因子（TGF-β、CTGF、Il-6）的表达水平差异最明显。氯沙坦的抗纤维化特性还不够显著，无法完全预防严重关节损伤后 PTJS 的发展。
