Histone deacetylase inhibition activates Nrf2 and protects against osteoarthritis.
Histone deacetylase inhibition activates Nrf2 and protects against osteoarthritis.
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组蛋白脱乙酰酶抑制激活 Nrf2 并预防骨关节炎
DOI：
10.1186/s13075-015-0774-3
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发表时间：
2015-09-26
影响因子：
4.9
通讯作者：
Cao W
中科院分区：
文献类型：
--
作者：
Cai D;Yin S;Yang J;Jiang Q;Cao W
骨关节炎（OA）是一种常见的关节疾病，可导致老年人逐渐残疾。核因子（红细胞衍生2）样2 （Nrf2）是调节II期抗氧化酶表达的关键转录因子，提供抗氧化应激和组织损伤的保护。使用组蛋白去乙酰化酶抑制剂（HDACi）已成为一种潜在的治疗多种疾病的策略。它们在各种关节炎动物模型中显示出软骨保护作用。先前的研究已经证实Nrf2乙酰化可以增强Nrf2的功能。在这里，我们探讨Nrf2在OA发展中的作用，以及Nrf2乙酰化在OA的HDACi保护中的作用。两种OA模型-碘乙酸钠（MIA）关节注射和内侧半月板不稳定(DMM) -用于野生型（WT）和Nrf2敲除（Nrf2- ko）小鼠，以证明Nrf2在OA进展中的作用。采用一种泛HDACi， trichostatin A (TSA)，观察HDACi对软骨损伤的保护效果。对组织学切片进行评分。检测oa相关基质金属蛋白酶（MMPs） 1、3、13及促炎因子肿瘤坏死因子(TNF)-α、白细胞介素(IL)-1β、IL-6的表达。比较HDACi对WT和Nrf2-KO小鼠OA的保护作用。Nrf2-KO小鼠在MIA和DMM模型中均表现出更严重的软骨损伤。TSA促进了SW1353软骨肉瘤细胞和小鼠关节组织中Nrf2下游蛋白的诱导。TSA还降低了oa相关蛋白MMP1、MMP3和MMP13以及促炎细胞因子TNF-α、IL-1β和IL-6的表达。TSA在两种OA模型中均能显著降低软骨损伤，但对Nrf2-KO小鼠无显著保护作用。Nrf2在骨性关节炎的进展中具有重要的软骨保护作用，是hdac介导的骨性关节炎保护的关键分子。
Osteoarthritis (OA) is a common joint disease that can cause gradual disability among the aging population. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a key transcription factor that regulates the expression of phase II antioxidant enzymes that provide protection against oxidative stress and tissue damage. The use of histone deacetylase inhibitors (HDACi) has emerged as a potential therapeutic strategy for various diseases. They have displayed chondroprotective effects in various animal models of arthritis. Previous studies have established that Nrf2 acetylation enhances Nrf2 functions. Here we explore the role of Nrf2 in the development of OA and the involvement of Nrf2 acetylation in HDACi protection of OA. Two OA models—monosodium iodoacetate (MIA) articular injection and destabilization of the medial meniscus (DMM)—were used with wild-type (WT) and Nrf2-knockout (Nrf2-KO) mice to demonstrate the role of Nrf2 in OA progression. A pan-HDACi, trichostatin A (TSA), was administered to examine the effectiveness of HDACi on protection from cartilage damage. The histological sections were scored. The expression of OA-associated matrix metalloproteinases (MMPs) 1, 3, and 13 and proinflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 were assayed. The effectiveness of HDACi on OA protection was compared between WT and Nrf2-KO mice. Nrf2-KO mice displayed more severe cartilage damage in both the MIA and DMM models. TSA promoted the induction of Nrf2 downstream proteins in SW1353 chondrosarcoma cells and in mouse joint tissues. TSA also reduced the expression of OA-associated proteins MMP1, MMP3, and MMP13 and proinflammatory cytokines TNF-α, IL-1β, and IL-6. TSA markedly reduced the cartilage damage in both OA models but offered no significant protection in Nrf2-KO mice. Nrf2 has a major chondroprotective role in progression of OA and is a critical molecule in HDACi-mediated OA protection.