Pleiotropic Effects of Simvastatin and Losartan in Preclinical Models of Post-Traumatic Elbow Contracture.
Pleiotropic Effects of Simvastatin and Losartan in Preclinical Models of Post-Traumatic Elbow Contracture.
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DOI：
10.3389/fbioe.2022.803403
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发表时间：
2022
影响因子：
5.7
通讯作者：
Lake SP
中科院分区：
文献类型：
--
作者：
David MA;Reiter AJ;Dunham CL;Castile RM;Abraham JA;Iannucci LE;Shah ID;Havlioglu N;Chamberlain AM;Lake SP
肘部创伤可导致创伤后关节挛缩（PTJC），其特征在于与关节囊/韧带纤维化和软骨损伤相关的运动丧失。不幸的是，目前的治疗往往是不成功的或引起并发症。本研究旨在确定预防性给予辛伐他汀（SV）和氯沙坦（LS）在肘部PTJC的两种临床前模型中的影响：体内肘部特异性大鼠损伤模型和体外胶原凝胶收缩试验。体内肘大鼠（n = 3-10/组）损伤模型评价了以两种给药策略口服施用SV和LS的作用[即，低剂量/高频率/短持续时间（D1）与高剂量/低频率/长持续时间（D2）]对死后肘关节活动范围（通过生物力学测试）以及关节囊纤维化和软骨损伤（通过组织病理学）的影响。结合活/死染色的体外凝胶收缩测定（n = 3-19/组）评价了SV和LS在各种浓度（即，1、10、100 µM）和持续时间（即，连续的、短的或延迟的）对成纤维细胞/肌成纤维细胞的收缩性和活力的影响[即，具有内源性转化生长因子β 1（TGFβ1）的NIH 3 T3成纤维细胞]。在体内，没有药物策略可以从生物力学上预防肘关节挛缩。在组织学上，只有SV-D2适度地减少了囊纤维化，但维持了升高的细胞结构和组织肥大，并且两种SV策略都减轻了软骨损伤。SV的适度受益局限于关节的前部区域，而不是后部。LS策略在关节囊和软骨中均无有意义的获益。在体外，无论是否存在TGFβ1，SV（≥10 μM）均部分通过降低细胞活力（100 μM）来阻止凝胶收缩。相比之下，LS不阻止凝胶收缩或影响细胞活力。这项研究表明，SV，而不是LS，可能是合适的预防性药物治疗在两个临床前模型的肘关节PTJC。结果提供了初步的见解，以指导未来的临床前研究，旨在预防或减轻肘关节PTJC。
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 in vivo elbow-specific rat injury model and an in vitro collagen gel contraction assay. The in vivo elbow rat (n = 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 (via biomechanical testing) as well as capsule fibrosis and cartilage damage (via histopathology). The in vitro gel contraction assay coupled with live/dead staining (n = 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)]. In vivo, 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. In vitro, 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.
DOI：
10.32098/mltj.03.2021.20
发表时间：
2021-07
期刊：
Muscles, ligaments and tendons journal
影响因子：
--
作者：
Reiter AJ;Castile RM;Schott HR;Kivitz GJ;Chamberlain AM;Lake SP
通讯作者：
Lake SP