4-Methylumbelliferone Diminishes Catabolically Activated Articular Chondrocytes and Cartilage Explants via a Mechanism Independent of Hyaluronan Inhibition
4-Methylumbelliferone Diminishes Catabolically Activated Articular Chondrocytes and Cartilage Explants via a Mechanism Independent of Hyaluronan Inhibition
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DOI：
10.1074/jbc.m115.709683
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发表时间：
2016-06-03
影响因子：
4.8
通讯作者：
Knudson, Warren
中科院分区：
文献类型：
--
作者：
Ishizuka, Shinya;Askew, Emily B.;Knudson, Warren
软骨蛋白多糖的耗竭是与骨关节炎相关的最早的事件之一。这种缺失通常伴随着另一种糖胺多聚糖--透明质酸的协调缺失。实验表明，软骨细胞缺乏与细胞相关的透明质酸，通过转换为促进分解代谢的代谢，包括增加内源性炎症介质的产生和增加基质金属蛋白酶的合成。透明质酸的营业额也有所增加。总而言之，这样的反应可能会建立一种自我延续的螺旋事件，以维持或延长促进分解代谢的状态。软骨细胞或软骨也可以被促炎细胞因子和介质激活，如IL-1β、肿瘤坏死因子α、脂多糖、纤维连接蛋白片段和透明质酸低聚糖。为了确定透明质酸丢失引起的软骨细胞激活的机制，需要一种不包括降解透明质酸的耗竭方法。近年来，几个实验室已经使用香豆素衍生物4-甲基伞形酮作为透明质酸生物合成的有效抑制剂，部分原因是它能够隔离细胞内的UDP-葡萄糖醛酸并抑制透明质酸合成酶的转录。然而，与我们的预期相反，尽管4-甲基伞形酮确实是透明质酸生物合成的抑制剂，但这种消耗并没有引起软骨细胞或软骨的激活。相反，4-甲基伞形酮直接和选择性地阻断与软骨细胞分解代谢前期状态相关的基因产物，并通过透明质酸抑制之前和独立于透明质酸抑制的机制做到这一点。这些数据表明，4-甲基伞形酮还有其他有用的用途来阻断促炎细胞激活事件，但使其用于定义与透明质酸相关的功能变得复杂。
Depletion of the cartilage proteoglycan aggrecan is one of the earliest events that occurs in association with osteoarthritis. This loss is often accompanied by a coordinate loss in another glycosaminoglycan, hyaluronan. Chondrocytes experimentally depleted of cell-associated hyaluronan respond by switching to a pro-catabolic metabolism that includes enhanced production of endogenous inflammatory mediators and increased synthesis of matrix metalloproteinases. Hyaluronan turnover is also increased. Together, such a response provides for possible establishment of a self-perpetuating spiral of events that maintains or prolongs the pro-catabolic state. Chondrocytes or cartilage can also be activated by treatment with pro-inflammatory cytokines and mediators such as IL-1 beta, TNF alpha, LPS, fibronectin fragments, and hyaluronan oligosaccharides. To determine the mechanism of chondrocyte activation due to hyaluronan loss, a depletion method was required that did not include degrading the hyaluronan. In recent years, several laboratories have used the coumarin derivative, 4-methylumbelliferone, as a potent inhibitor of hyaluronan biosynthesis, due in part to its ability to sequester intracellular UDP-glucuronic acid and inhibition of hyaluronan synthase transcription. However, contrary to our expectation, although 4-methylumbelliferone was indeed an inhibitor of hyaluronan biosynthesis, this depletion did not give rise to an activation of chondrocytes or cartilage. Rather, 4-methylumbelliferone directly and selectively blocked gene products associated with the pro-catabolic metabolic state of chondrocytes and did so through a mechanism preceding and independent of hyaluronan inhibition. These data suggest that 4-methylumbelliferone has additional useful applications to block pro-inflammatory cell activation events but complicates how it is used for defining functions related to hyaluronan.