Nanotechnol Rev 2018; 7(6): 541–553 Review Magdalena Matysiak-Kucharek*, Magdalena Czajka, Krzysztof Sawicki, Marcin Kruszewski and Lucyna Kapka-Skrzypczak Effect of nanoparticles on the expression and activity of matrix metalloproteinases https://doi.org/10.1515/ntrev-2018-0110 Received September 14, 2018; accepted October 11, 2018; previously 1 Introduction published online November 15, 2018 Matrix metallopeptidases, commonly known as matrix Abstract: Matrix metallopeptidases, commonly known metalloproteinases (MMPs), are zinc-dependent proteo- as matrix metalloproteinases (MMPs), are a group of pro- lytic enzymes whose primary function is the degradation teolytic enzymes whose main function is the remodeling and remodeling of extracellular matrix (ECM) compo- of the extracellular matrix. Changes in the activity of nents. ECM is a complex, dynamic structure that condi- these enzymes are observed in many pathological states, tions the proper tissue architecture. MMPs by digesting including cancer metastases. An increasing body of evi- ECM proteins eliminate structural barriers and allow dence indicates that nanoparticles (NPs) can lead to the cell migration. Moreover, by hydrolyzing extracellularly deregulation of MMP expression and/or activity both in released proteins, MMPs can change the activity of many vitro and in vivo. In this work, we summarized the current signal peptides, such as growth factors, cytokines, and state of knowledge on the impact of NPs on MMPs. The chemokines. MMPs are involved in many physiological literature analysis showed that the impact of NPs on MMP processes, such as embryogenesis, reproduction cycle, or expression and/or activity is inconclusive. NPs exhibit wound healing; however, their increased activity is also both stimulating and inhibitory effects, which might be associated with a number of pathological conditions, such dependent on multiple factors, such as NP size and coat- as diabetes, cardiovascular diseases and neurodegenera- ing or a cellular model used in the research. tive and autoimmune disorders. A particular attention is paid to the role of MMPs in the metastasis and progression Keywords: enzymes; extracellular matrix; metalloprotein- of malignant tumors. Increased expression and/or activity ases; nanoparticles. of MMPs significantly correlate with the ability to metasta- size and greater invasiveness in almost all types of human *Corresponding author: Magdalena Matysiak-Kucharek, cancers and worse prognosis [1]. Thus, MMPs become a Department of Molecular Biology and Translational Research, potential target for therapy. Hydroxamate-based MMP Institute of Rural Health, Lublin, Jaczewskiego 2, Lublin 20-090, inhibitors, such as batimastat, ilomastat, and marimas- Poland, e-mail: [email protected] tat, which contain the CONHOH group binding zinc atom Magdalena Czajka and Krzysztof Sawicki: Department of Molecular Biology and Translational Research, Institute of Rural Health, at the active site of MMP enzyme, are the first synthetic Lublin, Jaczewskiego 2, Lublin 20-090, Poland inhibitors of MMPs allowed for testing on cancer patients. Marcin Kruszewski: Department of Molecular Biology and Currently, various other synthetic MMP inhibitors, which Translational Research, Institute of Rural Health, Lublin, differ in chemical structure, activity, and pharmacokinet- Jaczewskiego 2, Lublin 20-090, Poland; Centre for Radiobiology and ics, are on the market or in various phases of clinical trials Biological Dosimetry, Institute of Nuclear Chemistry and Technology, [2, 3]. Despite oncology, MMP inhibitors are used also in Dorodna 16, Warsaw 03-195, Poland; and Department of Medical Biology and Translational Research, Faculty of Medicine, University other areas of medicine, for example, in diseases related of Information Technology and Management, Sucharskiego 2, to the central nervous system [4]. Rzeszów 35-225, Poland Nanotechnology is a rapidly developing field of Lucyna Kapka-Skrzypczak: Department of Molecular Biology science, resulting in a variety of applications in industry and Translational Research, Institute of Rural Health, Lublin, and everyday life. In medicine, big hope is paid in the use Jaczewskiego 2, Lublin 20-090, Poland; and Department of Medical Biology and Translational Research, Faculty of Medicine, University of nanomaterials in the treatment of various diseases. of Information Technology and Management, Sucharskiego 2, Nanomaterials are foreseen to be used as drug and/or radi- Rzeszów 35-225, Poland onuclide carriers but also as agents for direct treatment, 542 M. Matysiak-Kucharek et al.: Effect of nanoparticles on the expression and activity of matrix metalloproteinases such as thermotherapy and phototherapy, or even nano- signal peptide, prodomain, and catalytic domain, which bots directly killing cancer cells [5]. In contrast, increasing is responsible for the proteolytic activity of the enzyme body of evidence suggests that nanoparticles (NPs) might and contains zinc and calcium ions as a structural or cata- be toxic for mammalian cells or might have other adverse lytic moiety. Only two MMPs have this simple structure: effects, such as the promotion of cancer development and MMP7 and MMP26. The others comprise the hemopexin- metastasis [6, 7]. like domain and other domains specific for individual In the last few years, the impact of a number of dif- MMPs. Therefore, MMPs show significant variability at ferent NPs on selected metalloproteinases has been the level of tertiary protein structure, which in turn affects reported. NPs can modulate the expression and/or activ- their properties. MMPs can be divided into five main sub- ity of MMPs in two ways: either stimulating or inhibiting groups according to their substrate activity and mecha- them. This study is an attempt to summarize the current nism of action: matrilysins, collagenases, stromelysins, state of knowledge on the effect of nanomaterials on the gelatinases, and membrane MMPs; however, some MMPs expression and activity of MMPs, a key factor in tumor do not fit into any of these groups and are classified as metastasis. “others” (Figure 1). Currently, 23 human MMPs are known, but their numbering starts from 1 and ends at 28 but does not include numbers 4, 5, 6, 18, and 22 due to the dupli- cation of names of the same MMP discovered by different 2 General characteristics of MMPs research groups at the same time [8, 9]. Matrilysins, also called endometalloproteinases, Although MMPs are multidomain enzymes, all identified have the ability to degrade fibronectin, fibrinogen, MMPs in humans share the same structure that include and collagen type IV. This group contains MMP7 and MMPs with minimal structural domain Matrylisins: MMP7, MMP26 MMPs with hemopexin domain Collagenases: MMP1, MMP8, MMP13; Stromelysins: MMP3, MMP10; Metaloelastases: MMP12; Enemielisines: MMP20; MMPs with fibronectin module Other MMPs: MMP19, MMP27 Gelatinases: MMP2, MMP9 MMPs with furin recognition motif Other MMPs: MMP11, MMP28 MMPs with vitronectin domain Other MMPs: MMP21 MMPs with cytoplasmic tail and transmembrane domain Membrane MMPs type I, transmembrane- anchored: MMP14, MMP15, MMP16, MMP24 MMPs with GPI anchor Membrane MMPs type I, GPI-anchored: MMP17, MMP25 MMPs with cysteine array and IgG like domain Membrane MMPs type II: MMP23 Signal Catalytic Hemopexin Furin Transmembrane GPI IgG-like peptide domain domain recognition motif domain anchor domain Fibronectin Cysteine Signal Prodomain Hinge Vitronectin domain Cytoplasmic tail module array anchor Figure 1: Domain structure of metalloproteinases (own elaboration). M. Matysiak-Kucharek et al.: Effect of nanoparticles on the expression and activity of matrix metalloproteinases 543 MMP26, characterized by the simplest protein struc- MMPs [8–12]. MMP gene expression at the transcription ture. Collagenases, which include MMP1, MMP8, and level is also effectively inhibited by transforming growth MMP13, degrade gelatin and practically all collagen factor-β. In addition, it has been shown that transcription subtypes. Their structure is characterized by the pres- factors, such as nuclear factor-κB light-chain enhancer of ence of hemopexin domain, bonded by a flexible linker activated B cells [13] and signal transducers and activators with the catalytic domain. MMP10 and MMP3 belong to of transcription 3 [14], can significantly affect MMP mRNA stromelysins and share substrate specificity, hydrolyzing expression. It also indicated that epigenetic mechanisms numerous components of the ECM. MMP3 exhibits higher play an important role in MMP regulation [15]. proteolytic efficiency and is necessary for the activation MMPs are secreted from cells in a latent form of of several MMP proenzymes. Sometimes, MMP11 is also zymogens. The presence of prodomain allows maintain- included to stromelysins due to the similar substrate ing MMPs in an inactive form. The activation of zymogen specificity. However, its structure does not correspond to can be achieved in several ways: (1) by removal of the the other enzymes of this group. The next MMP group are prodomain by another endoproteinase, (2) by allosteric gelatinases, which include MMP2 and MMP9. Structur- change of the prodomain conformation, or (3) by change ally, proteins belonging to this group contain the catalytic of the bond between the prodomain and zinc ions in the domain composed of three fibronectin type II modules, enzyme active center. It has been shown that substances which strengthens substrate binding. This structure