Galectin-1 Couples Glycobiology to Inflammation in Osteoarthritis through the Activation of an NF-κB-Regulated Gene Network
Galectin-1 Couples Glycobiology to Inflammation in Osteoarthritis through the Activation of an NF-κB-Regulated Gene Network
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DOI：
10.4049/jimmunol.1501165
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发表时间：
2016-02-15
影响因子：
4.4
通讯作者：
Gabius, Hans-Joachim
中科院分区：
文献类型：
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作者：
Toegel, Stefan;Weinmann, Daniela;Gabius, Hans-Joachim
骨关节炎是一种退行性关节疾病，是导致成人残疾的主要原因之一。骨关节炎发病机制尚未完全阐明，这限制了当前的疾病管理和治疗。基于软骨细胞糖组和粘附/生长调节凝集素家族（即半乳糖凝集素）网络内失调的现象学证据，我们检验了 Galectin-1 与引起变性相关的假设。免疫组织化学分析证实，Galectin-1 上调与骨关节炎软骨和软骨下骨组织病理学以及退化严重程度相关（p < 0.0001，n = 29 名患者）。在体外，凝集素被分泌并与可被同源糖抑制的骨关节炎软骨细胞结合。聚糖依赖性 Galectin-1 结合诱导一系列疾病标志物，包括基质金属蛋白酶和激活的 NF-κ B，从而开启炎症基因特征 (p < 10 216)。使用专用抑制剂抑制 NF-kB 通路的不同成分会导致 Galectin-1 介导的转录激活出现剂量依赖性损害。变性效应物（例如三种基质金属蛋白酶）的分泌增强强调了数据的病理生理学相关性。因此，这项研究将 Galectin-1 确定为临床相关炎症反应基因的主要调节因子，通过 NF-kappa B 发挥作用。由于炎症对于骨关节炎中的软骨变性至关重要，因此该报告揭示了糖生物学与骨关节炎软骨变性的密切关系。
Osteoarthritis is a degenerative joint disease that ranks among the leading causes of adult disability. Mechanisms underlying osteoarthritis pathogenesis are not yet fully elucidated, putting limits to current disease management and treatment. Based on the phenomenological evidence for dysregulation within the glycome of chondrocytes and the network of a family of adhesion/growth-regulatory lectins, that is, galectins, we tested the hypothesis that Galectin-1 is relevant for causing degeneration. Immunohistochemical analysis substantiated that Galectin-1 upregulation is associated with osteoarthritic cartilage and subchondral bone histopathology and severity of degeneration (p < 0.0001, n = 29 patients). In vitro, the lectin was secreted and it bound to osteoarthritic chondrocytes inhibitable by cognate sugar. Glycan-dependent Galectin-1 binding induced a set of disease markers, including matrix metalloproteinases and activated NF-kappa B, hereby switching on an inflammatory gene signature ( p < 10 216). Inhibition of distinct components of the NF-kB pathway using dedicated inhibitors led to dose-dependent impairment of Galectin-1-mediated transcriptional activation. Enhanced secretion of effectors of degeneration such as three matrix metalloproteinases underscores the data's pathophysiological relevance. This study thus identifies Galectin-1 as a master regulator of clinically relevant inflammatory-response genes, working via NF-kappa B. Because inflammation is critical to cartilage degeneration in osteoarthritis, this report reveals an intimate relation of glycobiology to osteoarthritic cartilage degeneration.