David Michael A, Reiter Alex J, Dunham Chelsey L, Castile Ryan M, Abraham James A, Iannucci Leanne E, Shah Ishani D, Havlioglu Necat, Chamberlain Aaron M, Lake Spencer P
Department of Mechanical Engineering and Materials Science, Washington University in St. Louis, St. Louis, MO, United States.
Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States.
Front Bioeng Biotechnol. 2022 Feb 21;10:803403. doi: 10.3389/fbioe.2022.803403. eCollection 2022.
Elbow trauma can lead to post-traumatic joint contracture (PTJC), which is characterized by loss of motion associated with capsule/ligament fibrosis and cartilage damage. Unfortunately, current therapies are often unsuccessful or cause complications. This study aimed to determine the effects of prophylactically administered simvastatin (SV) and losartan (LS) in two preclinical models of elbow PTJC: an elbow-specific rat injury model and an collagen gel contraction assay. The elbow rat ( = 3-10/group) injury model evaluated the effects of orally administered SV and LS at two dosing strategies [i.e., low dose/high frequency/short duration (D1) vs. high dose/low frequency/long duration (D2)] on post-mortem elbow range of motion ( biomechanical testing) as well as capsule fibrosis and cartilage damage ( histopathology). The gel contraction assay coupled with live/dead staining ( = 3-19/group) evaluated the effects of SV and LS at various concentrations (i.e., 1, 10, 100 µM) and durations (i.e., continuous, short, or delayed) on the contractibility and viability of fibroblasts/myofibroblasts [i.e., NIH3T3 fibroblasts with endogenous transforming growth factor-beta 1 (TGFβ1)]. , no drug strategy prevented elbow contracture biomechanically. Histologically, only SV-D2 modestly reduced capsule fibrosis but maintained elevated cellularity and tissue hypertrophy, and both SV strategies lessened cartilage damage. SV modest benefits were localized to the anterior region, not the posterior, of the joint. Neither LS strategy had meaningful benefits in capsule nor cartilage. , irrespective of the presence of TGFβ1, SV (≥10 μM) prevented gel contraction partly by decreasing cell viability (100 μM). In contrast, LS did not prevent gel contraction or affect cell viability. This study demonstrates that SV, but not LS, might be suitable prophylactic drug therapy in two preclinical models of elbow PTJC. Results provide initial insight to guide future preclinical studies aimed at preventing or mitigating elbow PTJC.
肘部创伤可导致创伤后关节挛缩（PTJC），其特征是与关节囊/韧带纤维化和软骨损伤相关的活动丧失。不幸的是，目前的治疗方法往往不成功或会引起并发症。本研究旨在确定预防性给予辛伐他汀（SV）和氯沙坦（LS）在两种肘部PTJC临床前模型中的效果：一种是肘部特异性大鼠损伤模型，另一种是胶原凝胶收缩试验。肘部大鼠（每组n = 3 - 10）损伤模型评估了口服SV和LS在两种给药策略下[即低剂量/高频/短疗程（D1）与高剂量/低频/长疗程（D2）]对死后肘部活动范围（生物力学测试）以及关节囊纤维化和软骨损伤（组织病理学）的影响。凝胶收缩试验结合活/死染色（每组n = 3 - 19）评估了不同浓度（即1、10、100 μM）和持续时间（即持续、短期或延迟）的SV和LS对成纤维细胞/肌成纤维细胞[即具有内源性转化生长因子-β1（TGFβ1）的NIH3T3成纤维细胞]的收缩性和活力的影响。在生物力学方面，没有药物策略能预防肘部挛缩。在组织学上，只有SV - D2适度减少了关节囊纤维化，但细胞数量和组织肥大仍维持在较高水平，且两种SV策略都减轻了软骨损伤。SV的适度益处局限于关节的前部区域，而非后部。两种LS策略在关节囊或软骨方面均无显著益处。此外，无论是否存在TGFβ1，SV（≥10 μM）部分通过降低细胞活力（100 μM）来阻止凝胶收缩。相比之下，LS不能阻止凝胶收缩或影响细胞活力。本研究表明，在两种肘部PTJC临床前模型中，SV而非LS可能是合适的预防性药物治疗。研究结果为指导未来旨在预防或减轻肘部PTJC的临床前研究提供了初步见解。
