Department of Neuroscience, University of Connecticut Health Center, Farmington, Connecticut 06030, USA.
Am J Pathol. 2012 Jan;180(1):12-6. doi: 10.1016/j.ajpath.2011.09.008. Epub 2011 Oct 25.
Tissue inhibitors of metalloproteinases (TIMPs) are pleiotropic extracellular proteins. TIMPs are recognized as endogenous regulators of matrix metalloproteinases (MMPs), a large family of extracellular enzymes with proteolytic activities that participate in cellular homeostasis, adaptation, and tissue remodeling. In addition to their roles as endogenous potent MMP inhibitors, accumulating evidence indicates important physiological roles for TIMPs that are independent of their ability to block MMP activities. For instance, MMP-independent actions of TIMP-1 in the central nervous system have been implicated in synaptic plasticity, neuroprotection, oncogenesis, and oligodendrocyte differentiation. Expression of TIMP-1 is dramatically increased in response to a variety of injurious and inflammatory insults. In the context of disease pathogenesis, MMP and TIMP expression are interpreted with respect to the proteolytic consequences of increased MMP/TIMP ratios. Here, we provide an alternative perspective on the homeostatic balance of TIMP and MMP proteins, whereby consideration is given to the possible role of MMPs as cognate inhibitors of the signaling functions of TIMPs. Thus, MMPs may regulate the receptor-mediated actions of TIMPs, inasmuch as TIMPs are themselves inhibitors of MMP-mediated proteolytic activities. This broader view reflects our emerging understanding that TIMP signaling and MMP inhibition represent two important functions of TIMPs that have the potential to affect tissue pathology.
组织金属蛋白酶抑制剂（TIMP）是多功能细胞外蛋白。TIMP 被认为是基质金属蛋白酶（MMP）的内源性调节剂，MMP 是一大类具有蛋白水解活性的细胞外酶，参与细胞内稳态、适应和组织重塑。除了作为内源性强 MMP 抑制剂的作用外，越来越多的证据表明 TIMP 具有独立于其阻断 MMP 活性的重要生理作用。例如，TIMP-1 在中枢神经系统中的 MMP 非依赖性作用与突触可塑性、神经保护、肿瘤发生和少突胶质细胞分化有关。TIMP-1 的表达在受到各种损伤和炎症刺激后显著增加。在疾病发病机制方面，MMP 和 TIMP 的表达与增加的 MMP/TIMP 比值的蛋白水解后果有关。在这里，我们提供了 TIMP 和 MMP 蛋白的动态平衡的另一种观点，即考虑 MMP 作为 TIMP 信号功能的同源抑制剂的可能作用。因此，MMP 可能调节 TIMP 的受体介导作用，因为 TIMP 本身也是 MMP 介导的蛋白水解活性的抑制剂。这种更广泛的观点反映了我们对 TIMP 信号和 MMP 抑制代表 TIMP 的两个重要功能的新认识，这两个功能有可能影响组织病理学。
