MicroRNA-146a reduces IL-1 dependent inflammatory responses in the intervertebral disc.
MicroRNA-146a reduces IL-1 dependent inflammatory responses in the intervertebral disc.
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DOI：
10.1016/j.gene.2014.10.024
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发表时间：
2015-01-25
期刊：
影响因子：
3.5
通讯作者：
Im HJ
中科院分区：
文献类型：
--
作者：
Gu SX;Li X;Hamilton JL;Chee A;Kc R;Chen D;An HS;Kim JS;Oh CD;Ma YZ;van Wijnen AJ;Im HJ
由于miR-146 a在关节软骨细胞中的表达与骨关节炎（OA）相关，我们评估了miR-146 a是否与脊柱中的软骨退变相关。用miR-146 a模拟物转染来自牛尾椎间盘（IVD）的髓核（NP）细胞的单层培养物。为了引起炎症反应和分解代谢细胞外基质（ECM）降解，用白细胞介素-1（IL-1）共处理细胞。基于定量实时逆转录酶PCR（qRT-PCR）分析，miR-146 a的转染降低了NP细胞中IL-1诱导的炎性基因和分解代谢蛋白酶的mRNA水平。类似地，miR 146 a抑制IL-1诱导的基质金属蛋白酶和聚集蛋白聚糖酶的蛋白水平，如通过免疫印迹所揭示的。将来自野生型（WT）和miR-146 a敲除（KO）小鼠的椎间盘节段在存在或不存在IL-1的情况下离体培养3天。椎间盘器官培养物的组织学和免疫组织化学（IHC）分析显示，IL-1介导椎间盘髓核中蛋白聚糖（PG）含量和分解代谢蛋白（MMP-13和ADAMTS-5）原位水平的变化。然而，与WT盘相比，这些IL-1效应在miR-146 a KO盘中更明显。例如，miR-146 a的缺乏增加了用IL-1处理后MMP-13和ADAMTS-5阳性细胞的百分比。因此，miR-146 a似乎保护免受IL-1诱导的IVD变性和炎症。刺激内源性miR-146 a表达或外源性递送miRNA-146 a是可行的治疗策略，其可以减缓椎间盘退变并恢复细胞外基质产生和周转的正常稳态平衡。
Because miR-146a expression in articular chondrocytes is associated with osteoarthritis (OA), we assessed whether miR-146a is linked to cartilage degeneration in the spine. Monolayer cultures of nucleus pulposus (NP) cells from the intervertebral discs (IVD) of bovine tails were transfected with a miR-146a mimic. To provoke inflammatory responses and catabolic extracellular matrix (ECM) degradation, cells were co-treated with interleukin-1 (IL-1). Transfection of miR-146a decreases IL-1 induced mRNA levels of inflammatory genes and catabolic proteases in NP cells based on quantitative real-time reverse transcriptase PCR (qRT-PCR) analysis. Similarly, miR146a suppresses IL-1 induced protein levels of matrix metalloproteinases and aggrecanases as revealed by immunoblotting. Disc segments from wild type (WT) and miR-146a knockout (KO) mice were cultured ex vivo in the presence or absence of IL-1 for 3 days. Histological and immunohistochemical (IHC) analyses of disc organ cultures revealed that IL-1 mediates changes in proteoglycan (PG) content and in-situ levels of catabolic proteins (MMP-13 and ADAMTS-5) in the nucleus pulposus of the disc. However, these IL-1 effects are more pronounced in miR-146a KO discs compared to WT discs. For example, absence of miR-146a increases the percentage of MMP-13 and ADAMTS-5 positive cells after treatment with IL-1. Thus, miR-146a appears to protect against IL-1 induced IVD degeneration and inflammation. Stimulation of endogenous miR-146a expression or exogenous delivery of miRNA-146a are viable therapeutic strategies that may decelerate disc degeneration and regain a normal homeostatic balance in extracellular matrix production and turn-over.
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