基质金属蛋白酶：从分子机制到生理学、病理生理学和药理学。

Matrix Metalloproteinases: From Molecular Mechanisms to Physiology, Pathophysiology, and Pharmacology.

机构信息

Departments of Physiology and Pharmacology and Biochemistry and Molecular Biology, University of Calgary, Calgary, Canada (L.G.N.d.A., Y.E., S.C., D.Y., A.D.); Department of Physiology and Pharmacology, University of Western Ontario, London, Canada (S.G., H.T.); and Université Paris-Saclay, CEA, INRAE, Medicaments et Technologies pour la Santé, Gif-sur-Yvette, France (L.D.).

出版信息

Pharmacol Rev. 2022 Jul;74(3):712-768. doi: 10.1124/pharmrev.121.000349.

DOI:10.1124/pharmrev.121.000349

PMID:35738680

Abstract

The first matrix metalloproteinase (MMP) was discovered in 1962 from the tail of a tadpole by its ability to degrade collagen. As their name suggests, matrix metalloproteinases are proteases capable of remodeling the extracellular matrix. More recently, MMPs have been demonstrated to play numerous additional biologic roles in cell signaling, immune regulation, and transcriptional control, all of which are unrelated to the degradation of the extracellular matrix. In this review, we will present milestones and major discoveries of MMP research, including various clinical trials for the use of MMP inhibitors. We will discuss the reasons behind the failures of most MMP inhibitors for the treatment of cancer and inflammatory diseases. There are still misconceptions about the pathophysiological roles of MMPs and the best strategies to inhibit their detrimental functions. This review aims to discuss MMPs in preclinical models and human pathologies. We will discuss new biochemical tools to track their proteolytic activity in vivo and ex vivo, in addition to future pharmacological alternatives to inhibit their detrimental functions in diseases. SIGNIFICANCE STATEMENT: Matrix metalloproteinases (MMPs) have been implicated in most inflammatory, autoimmune, cancers, and pathogen-mediated diseases. Initially overlooked, MMP contributions can be both beneficial and detrimental in disease progression and resolution. Thousands of MMP substrates have been suggested, and a few hundred have been validated. After more than 60 years of MMP research, there remain intriguing enigmas to solve regarding their biological functions in diseases.

摘要

基质金属蛋白酶（MMP）于 1962 年首次被发现，因其能够降解胶原蛋白而得名。顾名思义，基质金属蛋白酶是能够重塑细胞外基质的蛋白酶。最近，MMP 已被证明在细胞信号转导、免疫调节和转录控制中发挥多种额外的生物学作用，所有这些作用都与细胞外基质的降解无关。在这篇综述中，我们将介绍 MMP 研究的里程碑和重大发现，包括 MMP 抑制剂的各种临床试验。我们将讨论大多数 MMP 抑制剂在治疗癌症和炎症性疾病方面失败的原因。人们对 MMP 的病理生理学作用以及抑制其有害功能的最佳策略仍存在误解。这篇综述旨在讨论临床前模型和人类病理中的 MMP。我们将讨论新的生化工具，以跟踪其在体内和体外的蛋白水解活性，以及抑制其在疾病中有害功能的未来药理学替代方法。