Expression and regulation of metalloproteinases and their inhibitors in intervertebral disc aging and degeneration.
Expression and regulation of metalloproteinases and their inhibitors in intervertebral disc aging and degeneration.
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DOI：
10.1016/j.spinee.2012.02.027
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发表时间：
2013-03
期刊：
影响因子：
--
通讯作者：
Kang JD
中科院分区：
文献类型：
--
作者：
Vo NV;Hartman RA;Yurube T;Jacobs LJ;Sowa GA;Kang JD
细胞外基质 (ECM) 的破坏会导致椎间盘退变 (IDD)，这是许多脊柱相关疾病的基础。基质金属蛋白酶 (MMP) 以及具有血小板反应蛋白基序的解整合素和金属蛋白酶 (ADAMTS) 被认为是负责椎间盘 (IVD) 中 ECM 降解的主要蛋白水解酶。总结目前有关 IVD 老化和 IDD 中 MMP、ADAMTS 和金属蛋白酶组织抑制剂 (TIMP) 基因表达和调控的文献。对人类 IDD 中 MMP、ADAMTS 和 TIMP 基因表达的综合文献综述，并报道了在人类和动物模型系统中控制其表达和活性的调控因子的研究。据报道，人类退化 IVD 中特定 MMP（MMP-1、-2、-3、-7、-8、-10 和 -13）和 ADAMTS（ADAMTS-1、-4 和 -15）的上调。然而，从已发表的相互矛盾的研究中，仍不清楚 ADAMTS-5（主要聚集蛋白聚糖酶）的表达是否会随着 IDD 的增加而增加。相对于非变性 IVD，金属蛋白酶 3 的组织抑制剂在人类变性 IVD 中表达下调，而 TIMP-1 表达上调。大量研究表明，MMP 和 ADAMTS 的表达水平受到多种因素的组合调节，包括机械、炎症和氧化应激，其中一些因素部分通过 p38 丝裂原激活蛋白激酶途径介导。遗传易感性在决定 MMP-1、-2、-3 和 -9 的基因表达方面也起着重要作用。 MMP 和 ADAMTS 表达以及酶活性的上调与椎间盘 ECM 破坏有关，从而导致 IDD 的发生。未来的 IDD 治疗取决于识别特定的 MMP 和 ADAMTS，它们的失调会导致椎间盘 ECM 的病理性蛋白水解。
Destruction of extracellular matrix (ECM) leads to intervertebral disc degeneration (IDD), which underlies many spine-related disorders. Matrix metalloproteinases (MMPs), and disintegrins and metalloproteinases with thrombospondin motifs (ADAMTSs) are believed to be the major proteolytic enzymes responsible for ECM degradation in the intervertebral disc (IVD). To summarize the current literature on gene expression and regulation of MMPs, ADAMTSs, and tissue inhibitors of metalloproteinases (TIMPs) in IVD aging and IDD. A comprehensive literature review of gene expression of MMP, ADAMTS, and TIMP in human IDD and reported studies on regulatory factors controlling their expressions and activities in both human and animal model systems. Upregulation of specific MMPs (MMP-1, -2, -3, -7, -8, -10, and -13) and ADAMTS (ADAMTS-1, -4, and -15) were reported in human degenerated IVDs. However, it is still unclear from conflicting published studies whether the expression of ADAMTS-5, the predominant aggrecanase, is increased with IDD. Tissue inhibitors of metalloproteinase-3 is downregulated, whereas TIMP-1 is upregulated in human degenerated IVDs relative to nondegenerated IVDs. Numerous studies indicate that the expression levels of MMP and ADAMTS are modulated by a combination of many factors, including mechanical, inflammatory, and oxidative stress, some of which are mediated in part through the p38 mitogen-activated protein kinase pathway. Genetic predisposition also plays an important role in determining gene expression of MMP-1, -2, -3, and -9. Upregulation of MMP and ADAMTS expression and enzymatic activity is implicated in disc ECM destruction, leading to the development of IDD. Future IDD therapeutics depends on identifying specific MMPs and ADAMTSs whose dysregulation result in pathological proteolysis of disc ECM.
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