Wolosowicz Marta, Prokopiuk Slawomir, Kaminski Tomasz W
Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15260, USA.
Faculty of Health Sciences, University of Lomza, 14 Akademicka St., 18-400 Łomża, Poland.
Int J Mol Sci. 2024 Dec 21;25(24):13691. doi: 10.3390/ijms252413691.
Matrix metalloproteinase-2 (MMP-2), a zinc-dependent enzyme, plays a critical role in the degradation and remodeling of the extracellular matrix (ECM). As a member of the gelatinase subgroup of matrix metalloproteinases, MMP-2 is involved in a variety of physiological processes, including tissue repair, wound healing, angiogenesis, and embryogenesis. It is primarily responsible for the degradation of type IV and V collagen, fibronectin, laminin, and elastin, which are essential components of the ECM. MMP-2 is secreted as an inactive pro-enzyme (proMMP-2) and activated through proteolytic cleavage, with its activity being precisely regulated by tissue inhibitors of metalloproteinases (TIMPs). Dysregulation of MMP-2 has been linked to a variety of pathological conditions, including cardiovascular diseases, diabetic complications, kidney diseases, and cancer. In cardiovascular diseases, it contributes to vascular remodeling, atherosclerosis, and aneurysms, while in fibrotic diseases, it mediates excessive ECM degradation leading to tissue scarring. In diabetes, elevated MMP-2 activity exacerbates complications such as nephropathy, retinopathy, and cardiovascular disease. In cancer, MMP-2 facilitates tumor invasion and metastasis by degrading ECM components and promoting angiogenesis. Despite its essential roles in both physiological and pathological processes, targeting MMP-2 for therapeutic purposes presents challenges due to its dual functions in tissue remodeling and repair, raising concerns about unplanned consequences such as impaired tissue healing or excessive tissue damage. These challenges underscore the need for future research to focus on developing selective modulators that can precisely balance their activity under specific disease environments. Clinical trials targeting MMP-2 modulation highlight the potential of gelatinase inhibitors, including those targeting MMP-2, to reduce tumor progression in fibrosarcoma, breast, and lung cancers. This paper reviews the structure, function, and regulation of MMP-2, its involvement in disease pathogenesis, and the potential challenges in the therapeutic implications of modulating its activity.
基质金属蛋白酶-2（MMP-2）是一种锌依赖性酶，在细胞外基质（ECM）的降解和重塑中起关键作用。作为基质金属蛋白酶明胶酶亚组的成员，MMP-2参与多种生理过程，包括组织修复、伤口愈合、血管生成和胚胎发生。它主要负责降解IV型和V型胶原蛋白、纤连蛋白、层粘连蛋白和弹性蛋白，这些都是ECM的重要组成部分。MMP-2以无活性的前体酶（proMMP-2）形式分泌，并通过蛋白水解切割激活，其活性受到金属蛋白酶组织抑制剂（TIMPs）的精确调节。MMP-2的失调与多种病理状况有关，包括心血管疾病、糖尿病并发症、肾脏疾病和癌症。在心血管疾病中，它促成血管重塑、动脉粥样硬化和动脉瘤，而在纤维化疾病中，它介导ECM过度降解导致组织瘢痕形成。在糖尿病中，MMP-2活性升高会加剧肾病、视网膜病变和心血管疾病等并发症。在癌症中，MMP-2通过降解ECM成分和促进血管生成促进肿瘤侵袭和转移。尽管它在生理和病理过程中都起着重要作用，但由于其在组织重塑和修复中的双重功能，将MMP-2作为治疗靶点面临挑战，引发了对诸如组织愈合受损或过度组织损伤等意外后果的担忧。这些挑战凸显了未来研究需要专注于开发能够在特定疾病环境下精确平衡其活性的选择性调节剂。针对MMP-2调节的临床试验突出了明胶酶抑制剂（包括那些靶向MMP-2的抑制剂）在减少纤维肉瘤、乳腺癌和肺癌肿瘤进展方面的潜力。本文综述了MMP-2的结构、功能和调节、其在疾病发病机制中的作用以及调节其活性的治疗意义方面的潜在挑战。
