Localization of degradative enzymes and their inhibitors in the degenerate human intervertebral disc
Localization of degradative enzymes and their inhibitors in the degenerate human intervertebral disc
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DOI：
10.1002/path.1608
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发表时间：
2004-09-01
影响因子：
7.3
通讯作者：
Hoyland, JA
中科院分区：
文献类型：
--
作者：
Le Maitre, CL;Freemont, AJ;Hoyland, JA
椎间盘细胞外基质（IVD）在衰老和退变过程中发生的组织学和生化变化已被广泛研究。然而，这些变化背后的机制尚不完全清楚。许多研究表明基质金属蛋白酶（MMPs）和ADAMTS参与了IVD退变，但很少有研究将这些酶的产生部位定位于退变椎间盘的细胞。本研究使用免疫组织化学技术来定位和量化不同程度退变的非退变和退变椎间盘中降解酶（MMPs 1、3和13以及ADAMTS 4）及其抑制剂（TIMPS 1、2和3）的产生。在所有研究的椎间盘中，产生这些酶及其抑制剂的细胞是髓核和纤维内环（AF）的软骨细胞样细胞，在AF外几乎没有免疫阳性。非退行性椎间盘显示表达降解酶MMP 1和ADAMTS 4的细胞数量较少，表明这些酶在正常体内平衡中起作用。非退变椎间盘未见mmp3或mmp13免疫阳性。在退变椎间盘中，MMPs 1、3、13和ADAMTS 4免疫阳性的细胞数量随着退变的严重程度而增加。降解酶的增加还伴随着对timp1和2免疫阳性的细胞数量的增加，而对timp3免疫阳性的细胞数量则没有增加。这项研究强调，尽管许多MMPs的表达随着变性而增加，但这伴随着它们的抑制剂的增加。然而，对ADAMTS 4有免疫反应的细胞数量随着变性的增加而增加，与其抑制剂timp3的增加并不平行。这一发现表明，聚集酶，而不是MMPs，可能是抑制椎间盘退变的治疗靶点。版权所有(C) 2004大不列颠和爱尔兰病理学会。约翰威利之子有限公司出版。
The histological and biochemical changes that occur in the extracellular matrix of the intervertebral disc (IVD) during ageing and degeneration have been investigated extensively. However, the mechanisms behind these changes are not fully understood. A number of studies have suggested the involvement of matrix metalloproteinases (MMPs) and ADAMTS in IVD degeneration, but few have localized the site of production of these enzymes to the cells of the degenerate disc. This study uses immunohistochemical techniques to localize and quantify the production of degrading enzymes (MMPs 1, 3, and 13, and ADAMTS 4) and their inhibitors (TIMPS 1, 2, and 3) within non-degenerate and degenerate discs of varying severity of degeneration. In all discs investigated, the cells that produced the enzymes and their inhibitors were the chondrocyte-like cells of the nucleus pulposus and inner annulus fibrosus (AF), with little immunopositivity in the outer AF. Non-degenerate discs showed low numbers of cells expressing the degradative enzymes MMP 1 and ADAMTS 4, suggesting a role for these enzymes in normal homeostasis. No MMP 3 or MMP 13 immunopositivity was observed in non-degenerate discs. In degenerate discs, the number of cells immunopositive for MMPs 1, 3, 13 and ADAMTS 4 increased with the severity of degeneration. This increase in degrading enzymes was also accompanied by increases in the number of cells immunopositive for TIMPs 1 and 2 but not TIMP 3. This study highlights that although the expression of a number of MMPs increases with degeneration, this is accompanied by an increase in their inhibitors. However, the increase in the number of cells immunoreactive for ADAMTS 4 with increasing degeneration was not paralleled by a rise in its inhibitor TIMP 3. This finding indicates that the aggrecanases, rather then the MMPs, are a possible therapeutic target for the inhibition of disc degeneration. Copyright (C) 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley Sons, Ltd.