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Bignon, Marine, Cathy Pichol-Thievend, Julie Hardouin, Marilyne Malbouyres, Nicolas Bréchot, Luiz Nasciutti, Alain Barret, et al. "Lysyl oxidase-like protein-2 regulates sprouting angiogenesis and type IV collagen assembly in the endothelial basement membrane." Blood 118, no. 14 (October 6, 2011): 3979–89. http://dx.doi.org/10.1182/blood-2010-10-313296.
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Abstract Sprouting angiogenesis is associated with extensive extracellular matrix (ECM) remodeling. The molecular mechanisms involved in building the vascular microenvironment and its impact on capillary formation remain elusive. We therefore performed a proteomic analysis of ECM from endothelial cells maintained in hypoxia, a major stimulator of angiogenesis. Here, we report the characterization of lysyl oxidase-like protein-2 (LOXL2) as a hypoxia-target expressed in neovessels and accumulated in the endothelial ECM. LOXL2 belongs to the lysyl oxidase family of secreted enzymes involved in ECM crosslinking. Knockdown experiments in Tg(fli1:egfp)y1 zebrafish embryos resulted in lack of intersegmental vessel circulation and demonstrated LOXL2 involvement in proper capillary formation. Further investigation in vitro by loss and gain of function experiments confirmed that LOXL2 was required for tubulogenesis in 3D fibrin gels and demonstrated that this enzyme was required for collagen IV assembly in the ECM. In addition, LOXL2 depletion down-regulated cell migration and proliferation. These data suggest a major role for LOXL2 in the organization of endothelial basal lamina and in the downstream mechanotransductive signaling. Altogether, our study provides the first evidence for the role of LOXL2 in regulating angiogenesis through collagen IV scaffolding.
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Eraso, Pilar, María J. Mazón, Victoria Jiménez, Patricia Pizarro-García, Eva P. Cuevas, Jara Majuelos-Melguizo, Jesús Morillo-Bernal, Amparo Cano, and Francisco Portillo. "New Functions of Intracellular LOXL2: Modulation of RNA-Binding Proteins." Molecules 28, no. 11 (May 30, 2023): 4433. http://dx.doi.org/10.3390/molecules28114433.
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Lysyl oxidase-like 2 (LOXL2) was initially described as an extracellular enzyme involved in extracellular matrix remodeling. Nevertheless, numerous recent reports have implicated intracellular LOXL2 in a wide variety of processes that impact on gene transcription, development, differentiation, proliferation, migration, cell adhesion, and angiogenesis, suggesting multiple different functions for this protein. In addition, increasing knowledge about LOXL2 points to a role in several types of human cancer. Moreover, LOXL2 is able to induce the epithelial-to-mesenchymal transition (EMT) process—the first step in the metastatic cascade. To uncover the underlying mechanisms of the great variety of functions of intracellular LOXL2, we carried out an analysis of LOXL2’s nuclear interactome. This study reveals the interaction of LOXL2 with numerous RNA-binding proteins (RBPs) involved in several aspects of RNA metabolism. Gene expression profile analysis of cells silenced for LOXL2, combined with in silico identification of RBPs’ targets, points to six RBPs as candidates to be substrates of LOXL2’s action, and that deserve a more mechanistic analysis in the future. The results presented here allow us to hypothesize novel LOXL2 functions that might help to comprehend its multifaceted role in the tumorigenic process.
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Dinca, Simion, Cody Wolf, Laura Bond, and Cheryl Jorcyk. "Abstract 3645: OSM-induced LOXL2 expression hinges on upregulation of c-Myc and promotes tumor growth and metastasis, IL-1beta plays synergistic role in LOXL2 expression." Cancer Research 83, no. 7_Supplement (April 4, 2023): 3645. http://dx.doi.org/10.1158/1538-7445.am2023-3645.
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Abstract Ductal carcinoma is the most commonly diagnosed breast cancer in women, the presence of metastases drops patient five-year survival from 95% to an abysmal 27%. This makes studying the mechanisms that promote metastasis of critical importance. Research shows that the extracellular matrix (ECM) of the tumor microenvironment (TME) plays an important role in invasive ductal carcinoma (IDC) progression and metastasis. Specifically; the density, stiffness, and orientation of collagen I fibers in the stroma all impact IDC motility, invasion, and metastasis. Lysyl oxidase-like 2 (LOXL2) is a secreted enzymatic protein that is implicit in ECM remodeling. By catalyzing an oxidative reaction in peptidyl lysine/hydroxylysine present on collagen I fibers, LOXL2 initiates crosslinking of the fibers. Our previous publication demonstrates that interleukin-6-related pro-inflammatory cytokine signaling, specifically oncostatin M (OSM), led to the overexpression and secretion of the LOXL2 enzyme. This increased the metastatic potential of IDC cells by promoting the crosslinking and alignment of collagen I fibers, which in turn led to increased invasion in 3D collagen I matrices. Thus, we hypothesize that OSM-induced LOXL2 expression, secretion, and subsequent collagen I fiber crosslinking and alignment, leads to an increase in IDC metastasis. In vivo studies utilizing nude athymic mice injected with either MCF7-Luc-EV control or MCF7-Luc-OSM overexpressing cells were performed in conjunction with LOXL2 inhibition using specially designed chow containing either LOXL2 SMI or control. Further analysis of OSM signaling pathways was performed in MCF7 and MDA-MB-468 IDC cells to determine mechanism for OSM induction of LOXL2. Our studies demonstrate that canonical OSM signaling pathways (pERK, pSTAT3, and pAKT) all contribute to LOXL2 expression in MCF7 cells suggesting a possible mediator protein we identified as c-Myc. Furthermore, OSM-induced LOXL2 played a significant role in OSM promoted tumor growth and metastasis as LOXL2 inhibition led to decreased tumor size and far less metastatic lesions. We also analyzed and confirmed a synergistic interaction between OSM and interleukin-1beta (IL-1β) in LOXL2 expression. These results confirm the significance of LOXL2 expression in OSM promoted metastasis and suggests LOXL2 would be an important target for future breast cancer therapies, specifically in patients with elevated levels of OSM. Furthermore, the synergistic interaction between OSM and IL-1β in LOXL2 expression suggests that patients with high levels of both cytokines are at even greater risk of metastasis, making these great markers for determining at risk IDC patients. Citation Format: Simion Dinca, Cody Wolf, Laura Bond, Cheryl Jorcyk. OSM-induced LOXL2 expression hinges on upregulation of c-Myc and promotes tumor growth and metastasis, IL-1beta plays synergistic role in LOXL2 expression. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3645.
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Jena, Manoj Kumar, and Jagadeesh Janjanam. "Role of extracellular matrix in breast cancer development: a brief update." F1000Research 7 (March 5, 2018): 274. http://dx.doi.org/10.12688/f1000research.14133.1.
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Evidence is increasing on the crucial role of the extracellular matrix (ECM) in breast cancer progression, invasion and metastasis with almost all mortality cases owing to metastasis. The epithelial-mesenchymal transition is the first signal of metastasis involving different transcription factors such as Snail, TWIST, and ZEB1. ECM remodeling is a major event promoting cancer invasion and metastasis; where matrix metalloproteinases (MMPs) such as MMP-2, -9, -11, and -14 play vital roles degrading the matrix proteins for cancer spread. The β-D mannuronic acid (MMP inhibitor) has anti-metastatic properties through inhibition of MMP-2, and -9 and could be a potential therapeutic agent. Besides the MMPs, the enzymes such as LOXL2, LOXL4, procollagen lysyl hydroxylase-2, and heparanase also regulate breast cancer progression. The important ECM proteins like integrins (b1-, b5-, and b6- integrins), ECM1 protein, and Hic-5 protein are also actively involved in breast cancer development. The stromal cells such as tumor-associated macrophages (TAMs), cancer-associated fibroblasts (CAFs), and adipocytes also contribute in tumor development through different processes. The TAMs become proangiogenic through secretion of VEGF-A and building vessel network for nourishment and invasion of the tumor mass. The latest developments of ECM involvement in breast cancer progression has been discussed in this review and this study will help researchers in designing future work on breast cancer pathogenesis and developing therapy targeted to the ECM components.
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Jena, Manoj Kumar, and Jagadeesh Janjanam. "Role of extracellular matrix in breast cancer development: a brief update." F1000Research 7 (June 12, 2018): 274. http://dx.doi.org/10.12688/f1000research.14133.2.
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Evidence is increasing on the crucial role of the extracellular matrix (ECM) in breast cancer progression, invasion and metastasis with almost all mortality cases owing to metastasis. The epithelial-mesenchymal transition is the first signal of metastasis involving different transcription factors such as Snail, TWIST, and ZEB1. ECM remodeling is a major event promoting cancer invasion and metastasis; where matrix metalloproteinases (MMPs) such as MMP-2, -9, -11, and -14 play vital roles degrading the matrix proteins for cancer spread. The β-D mannuronic acid (MMP inhibitor) has anti-metastatic properties through inhibition of MMP-2, and -9 and could be a potential therapeutic agent. Besides the MMPs, the enzymes such as LOXL2, LOXL4, procollagen lysyl hydroxylase-2, and heparanase also regulate breast cancer progression. The important ECM proteins like integrins (b1-, b5-, and b6- integrins), ECM1 protein, and Hic-5 protein are also actively involved in breast cancer development. The stromal cells such as tumor-associated macrophages (TAMs), cancer-associated fibroblasts (CAFs), and adipocytes also contribute in tumor development through different processes. The TAMs become proangiogenic through secretion of VEGF-A and building vessel network for nourishment and invasion of the tumor mass. The latest developments of ECM involvement in breast cancer progression has been discussed in this review and this study will help researchers in designing future work on breast cancer pathogenesis and developing therapy targeted to the ECM components.
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Cañes, Laia, Ingrid Martí-Pàmies, Carme Ballester-Servera, Adela Herraiz-Martínez, Judith Alonso, María Galán, J. Francisco Nistal, et al. "Neuron-derived orphan receptor-1 modulates cardiac gene expression and exacerbates angiotensin II-induced cardiac hypertrophy." Clinical Science 134, no. 3 (February 2020): 359–77. http://dx.doi.org/10.1042/cs20191014.
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Abstract Hypertensive cardiac hypertrophy (HCH) is a common cause of heart failure (HF), a major public health problem worldwide. However, the molecular bases of HCH have not been completely elucidated. Neuron-derived orphan receptor-1 (NOR-1) is a nuclear receptor whose role in cardiac remodelling is poorly understood. The aim of the present study was to generate a transgenic mouse over-expressing NOR-1 in the heart (TgNOR-1) and assess the impact of this gain-of-function on HCH. The CAG promoter-driven transgenesis led to viable animals that over-expressed NOR-1 in the heart, mainly in cardiomyocytes and also in cardiofibroblasts. Cardiomyocytes from TgNOR-1 exhibited an enhanced cell surface area and myosin heavy chain 7 (Myh7)/Myh6 expression ratio, and increased cell shortening elicited by electric field stimulation. TgNOR-1 cardiofibroblasts expressed higher levels of myofibroblast markers than wild-type (WT) cells (α 1 skeletal muscle actin (Acta1), transgelin (Sm22α)) and were more prone to synthesise collagen and migrate. TgNOR-1 mice experienced an age-associated remodelling of the left ventricle (LV). Angiotensin II (AngII) induced the cardiac expression of NOR-1, and NOR-1 transgenesis exacerbated AngII-induced cardiac hypertrophy and fibrosis. This effect was associated with the up-regulation of hypertrophic (brain natriuretic peptide (Bnp), Acta1 and Myh7) and fibrotic markers (collagen type I α 1 chain (Col1a1), Pai-1 and lysyl oxidase-like 2 (Loxl2)). NOR-1 transgenesis up-regulated two key genes involved in cardiac hypertrophy (Myh7, encoding for β-myosin heavy chain (β-MHC)) and fibrosis (Loxl2, encoding for the extracellular matrix (ECM) modifying enzyme, Loxl2). Interestigly, in transient transfection assays, NOR-1 drove the transcription of Myh7 and Loxl2 promoters. Our findings suggest that NOR-1 is involved in the transcriptional programme leading to HCH.
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Saito, T., K. Uzawa, M. Terajima, M. Shiiba, A. L. Amelio, H. Tanzawa, and M. Yamauchi. "Aberrant Collagen Cross-linking in Human Oral Squamous Cell Carcinoma." Journal of Dental Research 98, no. 5 (February 20, 2019): 517–25. http://dx.doi.org/10.1177/0022034519828710.
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Tumor progression is a complex process involving extracellular matrix (ECM) remodeling and stiffening. However, the mechanisms that govern these processes and their roles in tumor progression are still poorly understood. In this study, we performed bioinformatics, immunohistochemical, and biochemical analyses to examine if collagen cross-linking is associated with tumor stage and regional lymph node metastasis (RLNM) in oral squamous cell carcinoma (OSCC). We found that the genes encoding key enzymes for cross-linking are frequently overexpressed in oral, head, and neck cancers. Specifically, the enzymes lysyl hydroxylase 2 (LH2) or lysyl oxidase (LOX) and LOX-like 2 (LOXL2) were significantly upregulated in late-stage tumors and associated with poor patient prognosis. The protein levels of these enzymes in the primary human OSCC were also significantly increased in late-stage tumors and markedly elevated in the RLNM-positive tumors. Notably, while overall LOX/LOXL2-catalyzed collagen cross-links were enriched in late-stage and RLNM-positive tumors, LH2-mediated stable cross-links were significantly increased. To our knowledge, this is the first study to investigate the association of collagen cross-linking and expression of key enzymes regulating this process with OSCC stage. The data indicate a critical role for collagen cross-linking in OSCC tumor progression and metastasis, which may provide insights into development of novel therapeutic strategies to prevent OSCC progression.
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Zeltz, Cédric, Elena Pasko, Thomas R. Cox, Roya Navab, and Ming-Sound Tsao. "LOXL1 Is Regulated by Integrin α11 and Promotes Non-Small Cell Lung Cancer Tumorigenicity." Cancers 11, no. 5 (May 22, 2019): 705. http://dx.doi.org/10.3390/cancers11050705.
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Integrin α11, a stromal collagen receptor, promotes tumor growth and metastasis of non-small cell lung cancer (NSCLC) and is associated with the regulation of collagen stiffness in the tumor stroma. We have previously reported that lysyl oxidase like-1 (LOXL1), a matrix cross-linking enzyme, is down-regulated in integrin α11-deficient mice. In the present study, we investigated the relationship between LOXL1 and integrin α11, and the role of LOXL1 in NSCLC tumorigenicity. Our results show that the expression of LOXL1 and integrin α11 was correlated in three lung adenocarcinoma patient datasets and that integrin α11 indeed regulated LOXL1 expression in stromal cells. Using cancer-associated fibroblast (CAF) with either a knockdown or overexpression of LOXL1, we demonstrated a role for LOXL1 in collagen matrix remodeling and collagen fiber alignment in vitro and in vivo in a NSCLC xenograft model. As a consequence of collagen reorganization in NSCLC tumor stroma, we showed that LOXL1 supported tumor growth and progression. Our findings demonstrate that stromal LOXL1, under regulation of integrin α11, is a determinant factor of NSCLC tumorigenesis and may be an interesting target in this disease.
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Martín-López, Javier, Consuelo Pérez-Rico, Selma Benito-Martínez, Bárbara Pérez-Köhler, Julia Buján, and Gemma Pascual. "The Role of the Stromal Extracellular Matrix in the Development of Pterygium Pathology: An Update." Journal of Clinical Medicine 10, no. 24 (December 17, 2021): 5930. http://dx.doi.org/10.3390/jcm10245930.
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Pterygium is a benign fibrovascular lesion of the bulbar conjunctiva with frequent involvement of the corneal limbus. Its pathogenesis has been mainly attributed to sun exposure to ultraviolet-B radiation. Obtained evidence has shown that it is a complex and multifactorial process which involves multiple mechanisms such as oxidative stress, dysregulation of cell cycle checkpoints, induction of inflammatory mediators and growth factors, angiogenic stimulation, extracellular matrix (ECM) disorders, and, most likely, viruses and hereditary changes. In this review, we aim to collect all authors’ experiences and our own, with respect to the study of fibroelastic ECM of pterygium. Collagen and elastin are intrinsic indicators of physiological and pathological states. Here, we focus on an in-depth analysis of collagen (types I and III), as well as the main constituents of elastic fibers (tropoelastin (TE), fibrillins (FBNs), and fibulins (FBLNs)) and the enzymes (lysyl oxidases (LOXs)) that carry out their assembly or crosslinking. All the studies established that changes in the fibroelastic ECM occur in pterygium, based on the following facts: An increase in the synthesis and deposition of an immature form of collagen type III, which showed the process of tissue remodeling. An increase in protein levels in most of the constituents necessary for the development of elastic fibers, except FBLN4, whose biological roles are critical in the binding of the enzyme LOX, as well as FBN1 for the development of stable elastin. There was gene overexpression of TE, FBN1, FBLN5, and LOXL1, while the expression of LOX and FBLN2 and -4 remained stable. In conclusion, collagen and elastin, as well as several constituents involved in elastic fiber assembly are overexpressed in human pterygium, thus, supporting the hypothesis that there is dysregulation in the synthesis and crosslinking of the fibroelastic component, constituting an important pathogenetic mechanism for the development of the disease.
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Steppan, Jochen, Huilei Wang, Yehudit Bergman, Marcel J. Rauer, Siqi Tan, Sandeep Jandu, Kavitha Nandakumar, et al. "Lysyl oxidase-like 2 depletion is protective in age-associated vascular stiffening." American Journal of Physiology-Heart and Circulatory Physiology 317, no. 1 (July 1, 2019): H49—H59. http://dx.doi.org/10.1152/ajpheart.00670.2018.
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Vascular stiffening and its sequelae are major causes of morbidity and mortality in the elderly. The increasingly accepted concept of “smooth muscle cell (SMC) stiffness syndrome” along with matrix deposition has emerged in vascular biology to account for the mechanical phenotype of arterial aging, but the molecular targets remain elusive. In this study, using an unbiased proteomic analysis, we identified lysyl oxidase-like 2 (LOXL2) as a critical SMC mediator for age-associated vascular stiffening. We tested the hypothesis that loss of LOXL2 function is protective in aging-associated vascular stiffening. We determined that exogenous and endogenous nitric oxide markedly decreased LOXL2 abundance and activity in the extracellular matrix of isolated SMCs and LOXL2 endothelial cells suppress LOXL2 abundance in the aorta. In a longitudinal study, LOXL2+/− mice were protected from age-associated increase in pulse-wave velocity, an index of vascular stiffening, as occurred in littermate wild-type mice. Using isolated aortic segments, we found that LOXL2 mediates vascular stiffening in aging by promoting SMC stiffness, augmented SMC contractility, and vascular matrix deposition. Together, these studies establish LOXL2 as a nodal point for a new therapeutic approach to treat age-associated vascular stiffening. NEW & NOTEWORTHY Increased central vascular stiffness augments risk of major adverse cardiovascular events. Despite significant advances in understanding the genetic and molecular underpinnings of vascular stiffening, targeted therapy has remained elusive. Here, we show that lysyl oxidase-like 2 (LOXL2) drives vascular stiffening during aging by promoting matrix remodeling and vascular smooth muscle cell stiffening. Reduced LOXL2 expression protects mice from age-associated vascular stiffening and delays the onset of isolated systolic hypertension, a major consequence of stiffening.
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Martínez-González, José, Saray Varona, Laia Cañes, María Galán, Ana Briones, Victoria Cachofeiro, and Cristina Rodríguez. "Emerging Roles of Lysyl Oxidases in the Cardiovascular System: New Concepts and Therapeutic Challenges." Biomolecules 9, no. 10 (October 14, 2019): 610. http://dx.doi.org/10.3390/biom9100610.
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Lysyl oxidases (LOX and LOX-likes (LOXLs) isoenzymes) belong to a family of copper-dependent enzymes classically involved in the covalent cross-linking of collagen and elastin, a pivotal process that ensures extracellular matrix (ECM) stability and provides the tensile and elastic characteristics of connective tissues. Besides this structural role, in the last years, novel biological properties have been attributed to these enzymes, which can critically influence cardiovascular function. LOX and LOXLs control cell proliferation, migration, adhesion, differentiation, oxidative stress, and transcriptional regulation and, thereby, their dysregulation has been linked to a myriad of cardiovascular pathologies. Lysyl oxidase could modulate virtually all stages of the atherosclerotic process, from endothelial dysfunction and plaque progression to calcification and rupture of advanced and complicated plaques, and contributes to vascular stiffness in hypertension. The alteration of LOX/LOXLs expression underlies the development of other vascular pathologies characterized by a destructive remodeling of the ECM, such as aneurysm and artery dissections, and contributes to the adverse myocardial remodeling and dysfunction in hypertension, myocardial infarction, and obesity. This review examines the most recent advances in the study of LOX and LOXLs biology and their pathophysiological role in cardiovascular diseases with special emphasis on their potential as therapeutic targets.
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Meier, Alex A., Eden P. Go, Hee-Jung Moon, Heather Desaire, and Minae Mure. "Mass Spectrometry-Based Disulfide Mapping of Lysyl Oxidase-like 2." International Journal of Molecular Sciences 23, no. 11 (May 24, 2022): 5879. http://dx.doi.org/10.3390/ijms23115879.
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Lysyl oxidase-like 2 (LOXL2) catalyzes the oxidative deamination of peptidyl lysines and hydroxylysines to promote extracellular matrix remodeling. Aberrant activity of LOXL2 has been associated with organ fibrosis and tumor metastasis. The lysine tyrosylquinone (LTQ) cofactor is derived from Lys653 and Tyr689 in the amine oxidase domain via post-translational modification. Based on the similarity in hydrodynamic radius and radius of gyration, we recently proposed that the overall structures of the mature LOXL2 (containing LTQ) and the precursor LOXL2 (no LTQ) are very similar. In this study, we conducted a mass spectrometry-based disulfide mapping analysis of recombinant LOXL2 in three forms: a full-length LOXL2 (fl-LOXL2) containing a nearly stoichiometric amount of LTQ, Δ1-2SRCR-LOXL2 (SRCR1 and SRCR2 are truncated) in the precursor form, and Δ1-3SRCR-LOXL2 (SRCR1, SRCR2, SRCR3 are truncated) in a mixture of the precursor and the mature forms. We detected a set of five disulfide bonds that is conserved in both the precursor and the mature recombinant LOXL2s. In addition, we detected a set of four alternative disulfide bonds in low abundance that is not associated with the mature LOXL2. These results suggest that the major set of five disulfide bonds is retained post-LTQ formation.
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Barker, Holly E., Joan Chang, Thomas R. Cox, Georgina Lang, Demelza Bird, Monica Nicolau, Holly R. Evans, Alison Gartland, and Janine T. Erler. "LOXL2-Mediated Matrix Remodeling in Metastasis and Mammary Gland Involution." Cancer Research 71, no. 5 (January 13, 2011): 1561–72. http://dx.doi.org/10.1158/0008-5472.can-10-2868.
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Pichol-thievend, C., M. Bignon, S. Michineau, S. Ludwig, S. Germain, C. Monnot, M. Gervais, and L. Muller. "I016 Extracellular matrix remodelling in abdominal aortic aneurysm: involvement of LOXL2 and TG2 reticulation enzymes." Archives of Cardiovascular Diseases 102 (March 2009): S92. http://dx.doi.org/10.1016/s1875-2136(09)72350-2.
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Barker, Holly E., Joan Chang, Thomas R. Cox, Georgina Lang, Demelza Bird, Monica Nicolau, Holly R. Evans, Alison Gartland, and Janine T. Erler. "Correction: LOXL2-Mediated Matrix Remodeling in Metastasis and Mammary Gland Involution." Cancer Research 79, no. 19 (October 1, 2019): 5123. http://dx.doi.org/10.1158/0008-5472.can-19-2420.
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Meier, Alex A., Hee-Jung Moon, Ronald Toth, Ewa Folta-Stogniew, Krzysztof Kuczera, C. Russell Middaugh, and Minae Mure. "Oligomeric States and Hydrodynamic Properties of Lysyl Oxidase-Like 2." Biomolecules 11, no. 12 (December 8, 2021): 1846. http://dx.doi.org/10.3390/biom11121846.
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Lysyl oxidase-like 2 (LOXL2) has emerged as a promising therapeutic target against metastatic/invasive tumors and organ and tissue fibrosis. LOXL2 catalyzes the oxidative deamination of lysine and hydroxylysine residues in extracellular matrix (ECM) proteins to promote crosslinking of these proteins, and thereby plays a major role in ECM remodeling. LOXL2 secretes as 100-kDa full-length protein (fl-LOXL2) and then undergoes proteolytic cleavage of the first two scavenger receptor cysteine-rich (SRCR) domains to yield 60-kDa protein (Δ1-2SRCR-LOXL2). This processing does not affect the amine oxidase activity of LOXL2 in vitro. However, the physiological importance of this cleavage still remains elusive. In this study, we focused on characterization of biophysical properties of fl- and Δ1-2SRCR-LOXL2s (e.g., oligomeric states, molecular weights, and hydrodynamic radii in solution) to gain insight into the structural role of the first two SRCR domains. Our study reveals that fl-LOXL2 exists predominantly as monomer but also dimer to the lesser extent when its concentration is <~1 mM. The hydrodynamic radius (Rh) determined by multi-angle light scattering coupled with size exclusion chromatography (SEC-MALS) indicates that fl-LOXL2 is a moderately asymmetric protein. In contrast, Δ1-2SRCR-LOXL2 exists solely as monomer and its Rh is in good agreement with the predicted value. The Rh values calculated from a 3D modeled structure of fl-LOXL2 and the crystal structure of the precursor Δ1-2SRCR-LOXL2 are within a reasonable margin of error of the values determined by SEC-MALS for fl- and Δ1-2SRCR-LOXL2s in mature forms in this study. Based on superimposition of the 3D model and the crystal structure of Δ1-2SRCR-LOXL2 (PDB:5ZE3), we propose a configuration of fl-LOXL2 that explains the difference observed in Rh between fl- and Δ1-2SRCR-LOXL2s in solution.
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Rodríguez, Cristina, and José Martínez-González. "The Role of Lysyl Oxidase Enzymes in Cardiac Function and Remodeling." Cells 8, no. 12 (November 21, 2019): 1483. http://dx.doi.org/10.3390/cells8121483.
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Lysyl oxidase (LOX) proteins comprise a family of five copper-dependent enzymes (LOX and four LOX-like isoenzymes (LOXL1–4)) critical for extracellular matrix (ECM) homeostasis and remodeling. The primary role of LOX enzymes is to oxidize lysyl and hydroxylysyl residues from collagen and elastin chains into highly reactive aldehydes, which spontaneously react with surrounding amino groups and other aldehydes to form inter- and intra-catenary covalent cross-linkages. Therefore, they are essential for the synthesis of a mature ECM and assure matrix integrity. ECM modulates cellular phenotype and function, and strikingly influences the mechanical properties of tissues. This explains the critical role of these enzymes in tissue homeostasis, and in tissue repair and remodeling. Cardiac ECM is mainly composed of fibrillar collagens which form a complex network that provides structural and biochemical support to cardiac cells and regulates cell signaling pathways. It is now becoming apparent that cardiac performance is affected by the structure and composition of the ECM and that any disturbance of the ECM contributes to cardiac disease progression. This review article compiles the major findings on the contribution of the LOX family to the development and progression of myocardial disorders.
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Puente, Angela, Jose Fortea, Joaquin Cabezas, Maria Arias Loste, Paula Iruzubieta, Susana Llerena, Patricia Huelin, Emilio Fábrega, and Javier Crespo. "LOXL2—A New Target in Antifibrogenic Therapy?" International Journal of Molecular Sciences 20, no. 7 (April 2, 2019): 1634. http://dx.doi.org/10.3390/ijms20071634.
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The concept of liver fibrosis and cirrhosis being static and therefore irreversible is outdated. Indeed, both human and animal studies have shown that fibrogenesis is a dynamic and potentially reversible process that can be modulated either by stopping its progression and/or by promoting its resolution. Therefore, the study of the molecular mechanisms involved in the pathogenesis of liver fibrosis is critical for the development of future antifibrotic therapies. The fibrogenesis process, common to all forms of liver injury, is characterized by the increased deposition of extracellular matrix components (EMCs), including collagen, proteoglycans, and glycoproteins (laminin and fibronectin 2). These changes in the composition of the extracellular matrix components alter their interaction with cell adhesion molecules, influencing the modulation of cell functions (growth, migration, and gene expression). Hepatic stellate cells and Kupffer cells (liver macrophages) are the key fibrogenic effectors. The antifibrogenic mechanism starts with the activation of Ly6Chigh macrophages, which can differentiate into macrophages with antifibrogenic action. The research of biochemical changes affecting fibrosis irreversibility has identified lysyl oxidase-like 2 (LOXL2), an enzyme that promotes the network of collagen fibers of the extracellular matrix. LOXL2 inhibition can decrease cell numbers, proliferation, colony formations, and cell growth, and it can induce cell cycle arrest and increase apoptosis. The development of a new humanized IgG4 monoclonal antibody against LOXL2 could open the window of a new antifibrogenic treatment. The current therapeutic target in patients with liver cirrhosis should focus (after the eradication of the causal agent) on the development of new antifibrogenic drugs. The development of these drugs must meet three premises: Patient safety, in non-cirrhotic phases, down-staging or at least stabilization and slowing the progression to cirrhosis must be achieved; whereas in the cirrhotic stage, the objective should be to reduce fibrosis and portal pressure.
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Lee, Minwook, Hyeon-Ju Cho, Kyung-Soon Park, and Hae-Yun Jung. "ELK3 Controls Gastric Cancer Cell Migration and Invasion by Regulating ECM Remodeling-Related Genes." International Journal of Molecular Sciences 23, no. 7 (March 28, 2022): 3709. http://dx.doi.org/10.3390/ijms23073709.
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Current therapeutic strategies for gastric cancer, including surgery and chemotherapy improve patient survival; however, the survival rate of patients with metastatic gastric cancer is very low. The molecular mechanisms underlying the dissemination of gastric cancer cells to distant organs are currently unknown. Here, we demonstrate that the E26 transformation-specific (ETS) transcription factor ELK3 (ELK3) gene is required for the migration and invasion of gastric cancer cells. The ELK3 gene modulates the expression of extracellular matrix (ECM) remodeling-related genes, such as bone morphogenetic protein (BMP1), lysyl oxidase like 2 (LOXL2), Snail family transcriptional repressor 1 (SNAI1), serpin family F member 1 (SERPINF1), decorin (DCN), and nidogen 1 (NID1) to facilitate cancer cell dissemination. Our in silico analyses indicated that ELK3 expression was positively associated with these ECM remodeling-related genes in gastric cancer cells and patient samples. The high expressions of ELK3 and other ECM remodeling-related genes were also closely associated with a worse prognosis of patients with gastric cancer. Collectively, these findings suggest that ELK3 acts as an important regulator of gastric cancer cell dissemination by regulating ECM remodeling.
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Vallet, Sylvain D., and Sylvie Ricard-Blum. "Lysyl oxidases: from enzyme activity to extracellular matrix cross-links." Essays in Biochemistry 63, no. 3 (September 2019): 349–64. http://dx.doi.org/10.1042/ebc20180050.
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Abstract The lysyl oxidase family comprises five members in mammals, lysyl oxidase (LOX) and four lysyl oxidase like proteins (LOXL1-4). They are copper amine oxidases with a highly conserved catalytic domain, a lysine tyrosylquinone cofactor, and a conserved copper-binding site. They catalyze the first step of the covalent cross-linking of the extracellular matrix (ECM) proteins collagens and elastin, which contribute to ECM stiffness and mechanical properties. The role of LOX and LOXL2 in fibrosis, tumorigenesis, and metastasis, including changes in their expression level and their regulation of cell signaling pathways, have been extensively reviewed, and both enzymes have been identified as therapeutic targets. We review here the molecular features and three-dimensional structure/models of LOX and LOXLs, their role in ECM cross-linking, and the regulation of their cross-linking activity by ECM proteins, proteoglycans, and by inhibitors. We also make an overview of the major ECM cross-links, because they are the ultimate molecular readouts of LOX/LOXL activity in tissues. The recent 3D model of LOX, which recapitulates its known structural and biochemical features, will be useful to decipher the molecular mechanisms of LOX interaction with its various substrates, and to design substrate-specific inhibitors, which are potential antifibrotic and antitumor drugs.
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Mižíková, Ivana, Francesco Palumbo, Tamás Tábi, Susanne Herold, István Vadász, Konstantin Mayer, Werner Seeger, and Rory E. Morty. "Perturbations to lysyl oxidase expression broadly influence the transcriptome of lung fibroblasts." Physiological Genomics 49, no. 8 (August 1, 2017): 416–29. http://dx.doi.org/10.1152/physiolgenomics.00026.2017.
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Lysyl oxidases are credited with pathogenic roles in lung diseases, including cancer, fibrosis, pulmonary hypertension, congenital diaphragmatic hernia, and bronchopulmonary dysplasia (BPD). Lysyl oxidases facilitate the covalent intra- and intermolecular cross-linking of collagen and elastin fibers, thereby imparting tensile strength to the extracellular matrix (ECM). Alternative ECM-independent roles have recently been proposed for lysyl oxidases, including regulation of growth factor signaling, chromatin remodeling, and transcriptional regulation, all of which impact cell phenotype. We demonstrate here that three of the five lysyl oxidase family members, Lox, Loxl1, and Loxl2, are highly expressed in primary mouse lung fibroblasts compared with other constituent cell types of the lung. Microarray analyses revealed that small interfering RNA knockdown of Lox, Loxl1, and Loxl2 was associated with apparent changes in the expression of 134, 3,761, and 3,554 genes, respectively, in primary mouse lung fibroblasts. The impact of lysyl oxidase expression on steady-state Mmp3, Mmp9, Eln, Rarres1, Gdf10, Ifnb1, Csf2, and Cxcl9 mRNA levels was validated, which is interesting, since the corresponding gene products are relevant to lung development and BPD, where lysyl oxidases play a functional role. In vivo, the expression of these genes broadly correlated with Lox, Loxl1, and Loxl2 expression in a mouse model of BPD. Furthermore, β-aminopropionitrile (BAPN), a selective lysyl oxidase inhibitor, did not affect the steady-state mRNA levels of lysyl oxidase target genes, in vitro in lung fibroblasts or in vivo in BAPN-treated mice. This study is the first to report that lysyl oxidases broadly influence the cell transcriptome.
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Kotantaki, Panoraia, Florian Laforêts, Eleni Maniati, Chiara Berlato, Anna Malliouri, Michael John Devlin, Beatrice Malacrida, Samar Elorbany, Ranjit Manchanda, and Frances R. Balkwill. "Abstract 5957: Chemotherapy-induced extracellular matrix remodeling in HGSOC." Cancer Research 83, no. 7_Supplement (April 4, 2023): 5957. http://dx.doi.org/10.1158/1538-7445.am2023-5957.
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Abstract In this study we explored the effects of chemotherapy on the extracellular matrix of high-grade serous ovarian cancer metastasis (HGSOC) at structural-textural protein level and transcriptionally, in order to identify the microenvironmental features that accompany a successful response. We studied two murine orthotopic, transplantable syngeneic models of HGSOC, one that displays excellent response to carboplatin/paclitaxel (60577) and one that is resistant to treatment (HGS2)1. Using immunohistochemistry, we stained omental tumors from both models for the ECM components fibronectin (FN1), collagen 1A1 (COL1A1) and versican (VCAN), also using Masson’s Trichrome to stain for collagen. We analyzed their abundance, textural features (Haralick features) and structure with the image analysis softwares, QuPath and TWOMBLI respectively. A compilation of 44 ECM metrics, which we named the “structure index”, correlated with response to chemotherapy, as measured by reduction in omental tumor weight. In parallel, we performed RNAseq on the omental tumors, identifying clusters of genes that change over time with chemotherapy treatment of the responsive model 60577, while the chemoresistant model HGS2 displayed limited alteration of gene expression. We integrated RNAseq and ECM structure and texture data, and showed the structure index was correlated with 144 core matrisome genes. To identify potential therapeutic targets, we then focused our study on genes that remained highly expressed in resistant tumors post chemotherapy, but were originally low or decreased with treatment in the sensitive tumors. Members of the LOX and P4HA family were found amongst these genes. We confirmed by immunohistochemical analysis that expression of LOX, LOXL2, P4HA1 and P4HA2 was downregulated by chemotherapy in the 60577 chemo-sensitive tumors while their levels remained relatively unaffected in the resistant HGS2 tumors. This study refines our understanding of the mechanisms of microenvironmental chemoresistance in HGSOC, highlighting putative therapeutic targets to increase the efficacy of platinum-based chemotherapy in ovarian cancer. 1 Maniati, E. et al. Mouse Ovarian Cancer Models Recapitulate the Human Tumor Microenvironment and Patient Response to Treatment. Cell Rep 30, 525-540.e527, doi:10.1016/j.celrep.2019.12.034 (2020). Citation Format: Panoraia Kotantaki, Florian Laforêts, Eleni Maniati, Chiara Berlato, Anna Malliouri, Michael John Devlin, Beatrice Malacrida, Samar Elorbany, Ranjit Manchanda, Frances R. Balkwill. Chemotherapy-induced extracellular matrix remodeling in HGSOC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5957.
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Benson, Al Bowen, Zung Thai, Michael J. Hawkins, Douglas Werner, Hua Dong, Claudia Lee, and Johanna C. Bendell. "A phase II randomized, double-blinded, placebo-controlled study to evaluate the efficacy and safety of simtuzumab (GS-6624) combined with gemcitabine as first-line treatment for metastatic pancreatic adenocarcinoma." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): TPS4149. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.tps4149.
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TPS4149 Background: Lysyl oxidase-like molecule 2 (LOXL2) is an extracellular matrix enzyme that catalyzes the covalent cross-linking of collagen and is widely expressed across desmoplastic tumors. Simtuzumab (GS-6624) is a humanized antibody that specifically inhibits LOXL2 enzymatic activity. Inhibiting LOXL2 is expected to block formation of desmoplasia, which is thought to play an important role in tumor progression and metastasis. Methods: The primary objective and of the study is to compare the additive efficacy of simtuzumab vs. placebo in combination with gemcitabine as measured by improvement in progression free survival (PFS). The secondary objective is to compare the additive efficacy of simtuzumab vs. placebo as measured by overall survival (OS) and objective response rate. Study Design: The study is a randomized, double-blind, placebo controlled Phase 2 trial in subjects with metastatic pancreatic adenocarcinoma. A total of 234 subjects will be randomized to 200 mg simtuzumab, 700 mg simtuzumab, or placebo at a 1:1:1 ratio (78 subjects per treatment group) in combination with gemcitabine in cycles of 28 days. In each cycle, subjects will receive IV GS-6624 or placebo infused on Days 1 and 15, and IV gemcitabine (1000 mg/m2) on Days 1, 8, and 15. CT or MRI scans will be performed every 8 weeks to evaluate response to treatment. Subjects will continue courses of treatment every 28 days in the absence of disease progression or unacceptable toxicity. As of January 30, 2013, 162 subjects have been randomized. Clinical trial information: NCT01472198.
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Bazylev, Vladlen V., and Tatyana V. Kanaeva. "The role of matrix metalloproteinases in the myocardial remodeling." CardioSomatics 11, no. 3 (November 25, 2020): 22–28. http://dx.doi.org/10.26442/22217185.2020.3.200374.
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The main structural event in the development of heart failure is the myocardial remodeling. The extracellular matrix, that was knows as, considered an inert framework of cardiomyocytes, plays an important role in cardiac remodeling. The enzyme system, primarily responsible for the degradation of the extracellular matrix, is a matrix metalloproteinases (MMP). This review examines the evidence for the participation of MMP in the myocardial remodeling and recent studies of MMP as prognostic markers. Regulation of induction and/or activation of MMP are potential therapeutic targets.
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Yun, Heesu, Hee-Jeong Im, Chungyoul Choe, and Sangho Roh. "Effect of LOXL2 on metastasis through remodeling of the cell surface matrix in non-small cell lung cancer cells." Gene 830 (July 2022): 146504. http://dx.doi.org/10.1016/j.gene.2022.146504.
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Yun, Heesu, Hee-Jeong Im, Chungyoul Choe, and Sangho Roh. "Effect of LOXL2 on metastasis through remodeling of the cell surface matrix in non-small cell lung cancer cells." Gene 830 (July 2022): 146504. http://dx.doi.org/10.1016/j.gene.2022.146504.
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Yun, Heesu, Hee-Jeong Im, Chungyoul Choe, and Sangho Roh. "Effect of LOXL2 on metastasis through remodeling of the cell surface matrix in non-small cell lung cancer cells." Gene 830 (July 2022): 146504. http://dx.doi.org/10.1016/j.gene.2022.146504.
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Liu, Jun, Kelton A. Schleyer, Tyrel L. Bryan, Changjian Xie, Gustavo Seabra, Yongmei Xu, Arjun Kafle, et al. "Ultrasensitive small molecule fluorogenic probe for human heparanase." Chemical Science 12, no. 1 (2021): 239–46. http://dx.doi.org/10.1039/d0sc04872k.
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Faure, E., I. Bernabei, J. Wegrzyn, T. Hügle, N. Busso, and S. Nasi. "POS0402 LYSYL OXIDASE (LOX) AND LYSYL OXIDASE-LIKE 2 (LOXL2) CONTRIBUTE TO CARTILAGE CALCIFICATION DURING OSTEOARTHRITIS." Annals of the Rheumatic Diseases 82, Suppl 1 (May 30, 2023): 456.1–456. http://dx.doi.org/10.1136/annrheumdis-2023-eular.2528.
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BackgroundCartilage pathological calcification is a hallmark of osteoarthritis (OA), a degenerative disease characterized by articular cartilage degradation that leads to joint pain and impaired movement. We previously demonstrated that lysyl oxidase-like enzymes (LOX(L), which include five enzymes, LOX and LOXL1-4), that catalyze the crosslinking of collagen and elastin fibers of the extracellular matrix (ECM), play a crucial role in cartilage calcification (Bernabei et al, in preparation). Indeed, the pan-LOX(L) inhibitor BAPN decreased crystal production in chondrocytes, but the identification of the crucial LOX(L) involved in this process remained to be established.ObjectivesTo identify the specific LOX(L) involved in cartilage calcification during OA.MethodsIn vitro, murine chondrocytes (primary cells or ATDC5 cells) were cultured in normal medium ((Nt), DMEM high glucose + 10% FBS) or calcifying medium ((CM), BGJb +10% FBS+ 20mM β-glycerophosphate + 50μg/ml ascorbic acid). The expression of Lox was silenced using siRNA at 100nM ((siLox), OriGene). Gene expression was measured by qPCR. Calcium-containing crystals were evidenced by alizarin red staining and quantified by cetylpiridinium dissolution of crystals.In vivo, mice were subjected to meniscectomy (MNX) in the right knee or sham operated in the left.Ex vivo, cartilage explants from undamaged or damaged cartilage regions were obtained from 7 OA patients undergoing knee replacement surgery. Immunohistochemistry (IHC) was performed on murine knees and human cartilage sections ((anti-LOX or anti-LOXL2 rabbit polyclonal antibodies (Proteintech or Genetex respectively). Calcification was detected by Alizarin red staining on histological sections, and proteoglycan loss by safranin-O staining. Mouse gene expression data from primary articular chondrocytes treated with interleukin-1β (IL-1β) for 24h were obtained from GEO (identifier: GSE104793).ResultsLoxexpression was increased in murine chondrocytes stimulated with calcification medium (CM), but notLoxl2. Similarly, transcriptome data from primary mouse articular chondrocyte treated with IL-1β, revealed that bothLoxandLoxl2were markedly upregulated in treated cells. We then evaluated Lox and Loxl2 modulation by IHC in calcified cartilage in the MNX OA model. Both Lox and Loxl2 were increased in MNX cartilage compared to sham cartilage and at an even higher extent in osteophytes and in newly formed calcified deposits appearing in MNX knees. In human OA cartilage we found massive calcification and proteoglycan loss in damaged areas compared to undamaged. In line with murine data, we revealed increased LOX and LOXL2 expression in damaged human cartilage, both in chondrocytes and in the extracellular matrix in correspondence to calcified regions. Next, we performedin vitroLox RNA silencing using siLox or siControl RNA transfected ATDC5 cells (siLox cells or siCtrl cells). Lox expression was decreased by more than 80% in siLox cells compared to siCtrl cells. Most importantly, in CM, siLox cells calcified less as demonstrated by alizarin red quantification. Furthermore, gene expression data showed inhibition of calcification geneAnnexin 5by Lox silencing. In agreement, we found an increase of early differentiation genesSox9andCol2, along with significant downregulation of hypertrophic markerCol10. However, no effect by Lox silencing was found on fibrotic genes (Col1, Col3) and on pro-calcifying cytokine interleukin-6 (Il-6). Additionally, we revealed a trend towards decreased mitochondrial reactive oxygen species in siLox cells. Finally, Lox silencing decreased gene expression of the ECM catabolic enzymeMmp13.ConclusionOur data revealed that LOX and LOXL2 are increased in calcified areas of murine and human cartilage. Additionally,in vitroinhibition of Lox prevents at least in part, calcium-crystal deposition, chondrocyte hypertrophy, andMmp13catabolic enzyme expression. Altogether, our results suggest that both LOX and LOXL2 might play a role in cartilage calcification and OA.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of InterestsNone Declared.
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Kulesza, Monika, Aleksandra Kicman, Joanna Motyka, Tomasz Guszczyn, and Sławomir Ławicki. "Importance of Metalloproteinase Enzyme Group in Selected Skeletal System Diseases." International Journal of Molecular Sciences 24, no. 24 (December 5, 2023): 17139. http://dx.doi.org/10.3390/ijms242417139.
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Bone tissue is a dynamic structure that is involved in maintaining the homeostasis of the body due to its multidirectional functions, such as its protective, endocrine, or immunological role. Specialized cells and the extracellular matrix (ECM) are responsible for the remodeling of specific bone structures, which alters the biomechanical properties of the tissue. Imbalances in bone-forming elements lead to the formation and progression of bone diseases. The most important family of enzymes responsible for bone ECM remodeling are matrix metalloproteinases (MMPs)—enzymes physiologically present in the body’s tissues and cells. The activity of MMPs is maintained in a state of balance; disruption of their activity is associated with the progression of many groups of diseases, including those of the skeletal system. This review summarizes the current understanding of the role of MMPs in bone physiology and the pathophysiology of bone tissue and describes their role in specific skeletal disorders. Additionally, this work collects data on the potential of MMPs as bio-markers for specific skeletal diseases.
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Bruno, Gerard, Roxanne Todor, Isabel Lewis, and Douglas Chyatte. "Vascular extracellular matrix remodeling in cerebral aneurysms." Journal of Neurosurgery 89, no. 3 (September 1998): 431–40. http://dx.doi.org/10.3171/jns.1998.89.3.0431.
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Object. The occurrence of cerebral aneurysms has been linked to alterations in the extracellular matrix and to matrix-degrading proteases. The purpose of the present study was to determine whether active extracellular matrix remodeling occurs within cerebral aneurysms. Methods. Aneurysm tissue was collected from 23 patients (two of whom had a ruptured aneurysm and 21 of whom had an unruptured aneurysm) and compared with 11 control basilar arteries harvested at autopsy. Active proteinases capable of gelatin lysis were identified by performing in situ zymography in the presence and absence of a metalloproteinase inhibitor (ethylenediamine tetraacetic acid) and a serine proteinase inhibitor (phenylmethylsulfonyl fluoride). Immunohistochemical analysis was used to localize plasmin, tissue-type (t)—plasminogen activator (PA), urokinase-type (u)—PA, membranetype (MT1)—matrix metalloproteinase (MMP), MMP-2, MMP-9, and tenascin. Focal areas of gelatin lysis occurred in most cerebral aneurysm tissue samples (17 of 21), but rarely in control arteries (two of 11) (p = 0.002). Both serine proteinases and MMPs contributed to gelatin lysis; however, the MMPs were the predominant enzyme family. Plasmin (p = 0.04) and MT1-MMP (p = 0.04) were expressed in the aneurysm tissue but were unusual in control tissue. The MMP-2 was also expressed more commonly in aneurysm than in control tissue (p = 0.07). The MMP-9 and t-PA were expressed in both groups; however, different staining patterns were observed between aneurysm and control tissue. Tenascin staining was commonly present in both groups, whereas u-PA staining was rarely present. Conclusions. Aneurysm tissue demonstrates increased proteolytic activity capable of lysing gelatin and increased expression of plasmin, MT1-MMP, and MMP-2 when compared with normal cerebral arteries. This activity may contribute to focal degradation of the vascular extracellular matrix and may be related to aneurysm formation and growth.
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Kim, Jin-Hong, Gyuseok Lee, Yoonkyung Won, Minju Lee, Ji-Sun Kwak, Churl-Hong Chun, and Jang-Soo Chun. "Matrix cross-linking–mediated mechanotransduction promotes posttraumatic osteoarthritis." Proceedings of the National Academy of Sciences 112, no. 30 (July 13, 2015): 9424–29. http://dx.doi.org/10.1073/pnas.1505700112.
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Osteoarthritis (OA) is characterized by impairment of the load-bearing function of articular cartilage. OA cartilage matrix undergoes extensive biophysical remodeling characterized by decreased compliance. In this study, we elucidate the mechanistic origin of matrix remodeling and the downstream mechanotransduction pathway and further demonstrate an active role of this mechanism in OA pathogenesis. Aging and mechanical stress, the two major risk factors of OA, promote cartilage matrix stiffening through the accumulation of advanced glycation end-products and up-regulation of the collagen cross-linking enzyme lysyl oxidase, respectively. Increasing matrix stiffness substantially disrupts the homeostatic balance between chondrocyte catabolism and anabolism via the Rho–Rho kinase–myosin light chain axis, consequently eliciting OA pathogenesis in mice. Experimental enhancement of nonenzymatic or enzymatic matrix cross-linking augments surgically induced OA pathogenesis in mice, and suppressing these events effectively inhibits OA with concomitant modulation of matrix degrading enzymes. Based on these findings, we propose a central role of matrix-mediated mechanotransduction in OA pathogenesis.
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Shajib, Md Shafiullah, Kathryn Futrega, Travis Jacob Klein, Ross W. Crawford, and Michael Robert Doran. "Collagenase treatment appears to improve cartilage tissue integration but damage to collagen networks is likely permanent." Journal of Tissue Engineering 13 (January 2022): 204173142210742. http://dx.doi.org/10.1177/20417314221074207.
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When repairing cartilage defects a major challenge is achieving high-quality integration between the repair tissue and adjacent native cartilage. Matrix-rich cartilage is not easily remodeled, motivating several studies to trial enzyme treatment of the tissue interface to facilitate remodeling and integration. Studying and optimizing such processes is tedious, as well as potentially expensive, and thus simpler models are needed to evaluate the merits of enzyme treatment on cartilage tissue integration. Herein, we used engineered cartilage microtissues formed from bone marrow-derived stromal cells (BMSC) or expanded articular chondrocytes (ACh) to study the impact of enzyme treatment on cartilage tissue integration and matrix remodeling. A 5-min treatment with collagenase appeared to improve cartilage microtissue integration, while up to 48 h treatment with hyaluronidase did not. Alcian blue and anti-collagen II staining suggested that collagenase treatment did facilitate near seamless integration of cartilage microtissues. Microtissue sections were stained with Picrosirius red and characterized using polarized light microscopy, revealing that individual microtissues contained a collagen network organized in concentric shells. While collagenase treatment appeared to improve tissue integration, assessment of the collagen fibers with polarized light indicated that enzymatically damaged networks were not remodeled nor restored during subsequent culture. This model and these data paradoxically suggest that collagen network disruption is required to improve cartilage tissue integration, but that the disrupted collagen networks are unlikely to subsequently be restored. Future studies should attempt to limit collagen network disruption to the surface of the cartilage, and we recommend using Picrosirius red staining and polarized light to assess the quality of matrix remodeling and integration.
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Deryugina, Elena I., and James P. Quigley. "Cell Surface Remodeling by Plasmin: A New Function for an Old Enzyme." Journal of Biomedicine and Biotechnology 2012 (2012): 1–21. http://dx.doi.org/10.1155/2012/564259.
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Plasmin, one of the most potent and reactive serine proteases, is involved in various physiological processes, including embryo development, thrombolysis, wound healing and cancer progression. The proteolytic activity of plasmin is tightly regulated through activation of its precursor, plasminogen, only at specific times and in defined locales as well as through inhibition of active plasmin by its abundant natural inhibitors. By exploiting the plasminogen activating system and overexpressing distinct components of the plasminogen activation cascade, such as pro-uPA, uPAR and plasminogen receptors, malignant cells can enhance the generation of plasmin which in turn, modifies the tumor microenvironment to sustain cancer progression. While plasmin-mediated degradation and modification of extracellular matrix proteins, release of growth factors and cytokines from the stroma as well as activation of several matrix metalloproteinase zymogens, all have been a focus of cancer research studies for decades, the ability of plasmin to cleave transmembrane molecules and thereby to generate functionally important cleaved products which induce outside-in signal transduction, has just begun to receive sufficient attention. Herein, we highlight this relatively understudied, but important function of the plasmin enzyme as it is generatedde novoat the interface between cross-talking cancer and host cells.
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Pirri, Carmelo, Brasilina Caroccia, Andrea Angelini, Lucia Petrelli, Maria Piazza, Carlo Biz, Pietro Ruggieri, Raffaele De Caro, and Carla Stecco. "Evidence of Renin–Angiotensin System Receptors in Deep Fascia: A Role in Extracellular Matrix Remodeling and Fibrogenesis?" Biomedicines 10, no. 10 (October 17, 2022): 2608. http://dx.doi.org/10.3390/biomedicines10102608.
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Recent studies have shown that fascial fibroblasts are sensitive to different stimuli (biochemical or biophysical), promoting extracellular matrix remodeling, as well as synthetic activity. Moreover, the extensive literature on the renin–angiotensin system (RAS) reported its involvement in tissue remodeling. This study aimed to investigate the presence of RAS components in the deep fascia. Thoracolumbar fascia specimens were collected from 13 patients (age range: 25-75 years; seven males and five females) who had undergone elective spinal surgical procedures at the Orthopedic Clinic of the University of Padova. Gene expression analysis was performed to investigate the expression of Ang II type 1 receptor (AT1R), Ang II type 2 receptor (AT2R), MAS receptor (MasR), angiotensinogen, angiotensin-converting enzyme 2 (ACE2) and angiotensin-converting enzyme 1 (ACE1). AT1R and ACE2 were also measured with immunoblot. AT1R was the most expressed angiotensin receptor subtype (300.2 ± 317 copies/25ng of mRNA), followed by MasR (37.1 ± 39.56 copies/25ng of mRNA) and AT2R (147 ± 122 copies/25ng of mRNA). The amounts of angiotensinogen, ACE1 and ACE2 were hardly detectable. These findings demonstrate that RAS system receptors are present in the deep fascia, with a greater expression of AT1R, suggesting their involvement in fascial remodeling and fibrogenesis.
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Luo, Lu-yuan, Si-qi Gu, Wan-xing Zhou, Li-zhi Chen, Xin-chao You, Rui-ying Li, Wei Zhang, and Yu-lan Song. "Recombinant Matrix Metalloproteinase-9 Induces Ventricular Remodeling By Up-Regulating Angiotensin II." American Journal of Hypertension 33, no. 2 (February 2020): 205–6. http://dx.doi.org/10.1093/ajh/hpz189.
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Abstract Objective To study the effect of matrix metalloproteinase-9 (MMP-9) on ventricular remodeling and involvement of angiotensin II (Ang II). Methods Thirty-six adult male Wistar rats were randomly divided into control (n = 12), MMP-9 (n = 12), and MMP-9 + olmesartan (n = 12) groups. Recombinant MMP-9 (2.1 ng/g) was injected intraperitoneally twice a week. Olmesartan (3 mg/kg) was given by oral gavage once daily. Animals were treated for 4 or 8 weeks. Cardiac function was assessed by echocardiography followed by histological analysis. The messenger RNA (mRNA) and protein levels of MMP-9 in myocardial tissues were analyzed by reverse transcription polymerase chain reaction and Western blotting, respectively. Serum levels of Ang I, II, angiotensin converting enzyme (ACE) and MMP-9 were determined by enzyme-linked immunosorbent assay (ELISA). Results MMP9 administration for 4 or 8 weeks increased mRNA and protein levels of MMP-9 in myocardial tissues, serum levels of MMP-9, Ang I, II and ACE, and left ventricular mass index (LVMI) but decreased collagen volume fraction (CVF) compared with the control group (all P < 0.05). Cardiomyocyte cell size was significantly enlarged and disorganized with cytoplasmic lysis and necrosis in the MMP-9 group. After olmesartan treatment, myocardial MMP-9 mRNA and protein levels, serum levels of MMP-9 and Ang II, and LVMI were lower, and CVF was higher with significant improvement in myocardial morphology and cardiac function (all P<0.05). Conclusion Recombinant MMP-9 treatment induces ventricular remodeling and cardiac dysfunction by up-regulating Ang II.
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Faust, Isabel, Philipp Traut, Cornelius Knappe, and Doris Hendig. "Pathobiochemistry of arthrofibrotic remodeling." Orthopaedic Journal of Sports Medicine 5, no. 4_suppl4 (April 1, 2017): 2325967117S0015. http://dx.doi.org/10.1177/2325967117s00151.
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Aims and Objectives: Arthrofibrosis is defined as painful impairment of joint flexibility due to fibrotic tissue remodeling after joint trauma or surgery. The incidence of arthrofibrosis after knee replacement surgery is 5 to 10%. Although conventional therapeutic approaches as for instance mobilization and physiotherapy are applied, an effective and causative therapeutic regimen is not known. Materials and Methods: To characterize arthrofibrotic remodeling of the extracellular matrix, to develop new therapeutic approaches and to define diagnostic biomarkers and therapeutic targets, understanding of biochemical principles is urgently required. Fibrotic remodeling was described in several tissues, whereas synovial fibrosis is one of the least investigated fibrotic disorders. Nevertheless, molecular key events in fibrosis seem to be the same and are initiated by exogenic or endogenic tissue damage and differentiation of resident fibroblasts of the connective tissue to myofibroblasts. Known inductors of myofibroblast differentiation are fibrotic growth factors, which are secreted by platelets, damaged tissue and inflammatory cells, as well as mechanical strain. Research studies concerning cardiac fibrosis in tako-tsubo cardiomyopathy also define emotional stress and sympathicotonic destabilization as profibrotic stressors. Myofibroblasts generate contractile forces and synthesize extracellular matrix components, so that scar tissue accumulates. While myofibroblasts disappear by apoptosis in physiological wound healing, they persist in fibrosis. Results: Recently, we could demonstrate that increased expression of human xylosyltransferase (XT)-I, an enzyme which catalyzes the rate limiting step in proteoglycan glycosylation, is linked to abnormal extracellular matrix remodeling. Serum XT activity reflects proteoglycan synthesis rate and is known as fibrosis biomarker in liver fibrosis or scleroderma. Our data also indicate that XT-I is a cellular key mediator of arthrofibrosis. However, we suggest that molecular changes based on arthrofibrosis are, due to local restriction of the affected joint by the blood-synovial-barrier, not detectable in human serum. Currently, we study synovial XT activity of arthrofibrosis patients and controls in a multicenter study. Conclusion: In summary, we give insights into the complex pathobiochemistry of arthrofibrosis as well as current research projects. A deeper characterization of the involved mechanisms might not only contribute to control and inhibit fibrotic remodeling by interfering with components of fibrotic signal cascades but also to establish new therapeutic strategies.
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Song, L., P. L. Ryan, D. G. Porter, and B. L. Coomber. "Effects of relaxin on matrix remodeling enzyme activity of cultured equine ovarian stromal cells." Animal Reproduction Science 66, no. 3-4 (May 2001): 239–55. http://dx.doi.org/10.1016/s0378-4320(01)00100-2.
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Shambatov, M. A., N. V. Izmozherova, A. A. Popov, I. F. Grishina, E. V. Kudryavtseva, V. V. Bazarnyi, L. G. Polushina, and M. A. Kopenkin. "Markers of Collagen Degradation in Remodeling and Diastolic Dysfunction of Left Ventricle in Patients with Arterial Hypertension." Ural Medical Journal 23, no. 1 (March 6, 2024): 46–59. http://dx.doi.org/10.52420/2071-5943-2024-23-1-46-59.
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Introduction. Myocardial remodeling is a consequence or predictor of several cardiovascular diseases. The key process in myocardial remodeling is the degradation of collagen fibers, mediated by the activity of matrix metalloproteinases and their tissue inhibitor.The aim of this study was to evaluate serum levels of matrix metalloproteinase type 9 and tissue inhibitor of matrix metalloproteinase type 1 in female patients with arterial hypertension, myocardial remodeling, and diastolic dysfunction.Materials and methods. A cross-sectional study that included 84 postmenopausal women. All patients underwent echocardiography. Left ventricular remodeling was assessed according to Ganau classification, and diastolic function was evaluated using transmittal flow parameters. Serum analysis included the determination of MMP-9 and TIMP-1 levels using an enzyme-linked immunosorbent assay.Results. The median concentration of MMP-9 in the sample was 2 295.00 (923.60–4 114.00) ng/ml, TIMP — 1–17 010.00 (16 780.00–17 170.00) ng/ml. When evaluating the echocardiographic parameters of the patients included in the study, changes were revealed that indicate structural and functional remodeling of the LV and DD. 29 patients (35 %) had normal geometry, 6 patients (7 %) had concentric myocardial remodeling, 21 patients (25 %) had concentric myocardial hypertrophy, 28 cases (33 %) had eccentric myocardial hypertrophy. Statistically significant changes in the activity of MMP-9 and TIMP-1 were revealed in patients with various structural and geometric variants of remodeling. DD was detected in all patients included in the study: I degree was detected in 25 patients (30 %), II degree was determined in 59 cases (70 %). Using one-way analysis of variance, statistically significant differences in the level of MMP-9 in patients with grades I and II DD were determined. MMP-9 and MMP-9/TIMP-1 in patients with grade II DD are significantly higher than in patients with grade I.Discussion. Under pathophysiological conditions, the proteolytic properties of MMP-9 contribute to the stimulation of the immune response, initiating pathogenesis and aggravating the progression of the disease. Evaluation of the activity of MMP-9 and TIMP-1 in patients with arterial hypertension may be a marker of myocardial remodeling.Conclusion. An increase in the activity of matrix metalloproteinase type 9 and a decrease in the activity of a tissue inhibitor of matrix metalloproteinases type 1 were revealed in patients with arterial hypertension, myocardial remodeling and LV diastolic dysfunction. The level of MMP-9 is associated with the degree of diastolic dysfunction and the structural-geometric type of LV remodeling.
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Beletskaya, Inessa Stanislavovna, and Sergey Yurievich Astakhov. "The role of matrix metalloproteinases in glaucoma pathogenesis." Ophthalmology journal 8, no. 3 (December 15, 2015): 28–43. http://dx.doi.org/10.17816/ov2015328-43.
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Matrix metalloproteinases belong to an enzyme family, which assure a proteolysis of practically all components of the extracellular matrix of connective tissues in normal and pathological conditions. At physiological conditions, there are evidences on the impact of this enzyme group in the embryogenesis, morphogenesis, angiogenesis, and tissue involution. The activity impairment of matrix metalloproteinases and of their specific inhibitors leads to the biosynthesis misbalance and to the degradation of extracellular matrix components; it plays a role in the development of such diseases as diabetes mellitus, rheumatoid arthritis, and arteriosclerosis. Laboratory tests and clinical investigation results confirm the role of these enzymes in tissue remodeling of different eyeball structures in glaucoma (in particular, of the trabecular meshwork and the optic disc); it leads to intraocular fluid outflow impairment and to the glaucomatous optic neuropathy development. In the review, the analysis of clinical and experimental studies is performed that are dedicated to the investigation of matrix metalloproteinases role in the pathogenesis of different glaucoma types, of the possibility to use them as biomarkers, as well as therapeutic action targets in this disease.
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Ribot, Jérôme, Rachel Breton, Charles-Félix Calvo, Julien Moulard, Pascal Ezan, Jonathan Zapata, Kevin Samama, et al. "Astrocytes close the mouse critical period for visual plasticity." Science 373, no. 6550 (July 1, 2021): 77–81. http://dx.doi.org/10.1126/science.abf5273.
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Brain postnatal development is characterized by critical periods of experience-dependent remodeling of neuronal circuits. Failure to end these periods results in neurodevelopmental disorders. The cellular processes defining critical-period timing remain unclear. Here, we show that in the mouse visual cortex, astrocytes control critical-period closure. We uncover the underlying pathway, which involves astrocytic regulation of the extracellular matrix, allowing interneuron maturation. Unconventional astrocyte connexin signaling hinders expression of extracellular matrix–degrading enzyme matrix metalloproteinase 9 (MMP9) through RhoA–guanosine triphosphatase activation. Thus, astrocytes not only influence the activity of single synapses but also are key elements in the experience-dependent wiring of brain circuits.
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Zaffryar-Eilot, Shelly, and Peleg Hasson. "Lysyl Oxidases: Orchestrators of Cellular Behavior and ECM Remodeling and Homeostasis." International Journal of Molecular Sciences 23, no. 19 (September 27, 2022): 11378. http://dx.doi.org/10.3390/ijms231911378.
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Lysyl oxidases have long been considered key secreted extracellular matrix modifying enzymes. As such, their activity has been associated with the crosslinking of collagens and elastin, and as a result, they have been linked to multiple developmental and pathological processes. However, numerous lines of evidence also demonstrated that members of this enzyme family are localized and are active within the cytoplasm or cell nuclei, where they regulate and participate in distinct cellular events. In this review, we focus on a few of these events and highlight the intracellular role these enzymes play. Close examination of these events, suggest that the intracellular activities of lysyl oxidases is mostly observed in processes where concomitant changes in the extracellular matrix takes place. Here, we suggest that the LOX family members act in the relay between changes in the cells’ environment and the intracellular processes that promote them or that follow.
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Obiezu, Chistina V., Iacovos P. Michael, Michael A. Levesque, and Eleftherios P. Diamandis. "Human kallikrein 4: enzymatic activity, inhibition, and degradation of extracellular matrix proteins." Biological Chemistry 387, no. 6 (June 1, 2006): 749–59. http://dx.doi.org/10.1515/bc.2006.094.
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AbstractHuman kallikrein 4 (hK4) is a member of the expanded family of human kallikreins, a group of 15 secreted proteases. While this protein has been associated with ovarian and prostate cancer prognosis, only limited functional information exists. Therefore, we have undertaken an investigation of its enzymatic properties regarding substrate preference, degradation of extracellular matrix proteins, and its inhibition by various inhibitors. We successfully expressed and purified active recombinant hK4 from supernatants of thePichia pastorisexpression system. This enzyme seems to cleave more efficiently after Arg compared to Lys at the P1 position and exhibits modest specificity for amino acids at positions P2 and P3. hK4 forms complexes with α1-antitrypsin, α2-antiplasmin and α2-macroglobulin. The protease mediates limited degradation of extracellular matrix proteins such as collagen I and IV, and more efficient degradation of the α-chain of fibrinogen. The cleavage of extracellular matrix proteins by hK4 suggests that this enzyme may play a role in tissue remodeling and cancer metastasis.
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Fang, Hong, Wei Chen, Yang Gao, Yi Shen, and Ming Luo. "Molecular Mechanisms Associated with Angiotensin-Converting Enzyme-Inhibitory Peptide Activity on Vascular Extracellular Matrix Remodeling." Cardiology 127, no. 4 (2014): 247–55. http://dx.doi.org/10.1159/000356951.
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Ribagin, Lora S., and Maya R. Rashkova. "Matrix Metalloproteinase-8 And Interleukin-1Β In Gingival Fluid Of Children In The First Three Months Of Orthodontic Treatment With Fixed Appliances." Folia Medica 54, no. 3 (September 1, 2012): 50–56. http://dx.doi.org/10.2478/v10153-011-0097-3.
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Abstract In orthodontic treatment remodeling of periodontal space is concomitant with the movement of teeth. Matrix metalloproteinase-8 and interleukin-1β are key markers of the initial tissue reaction in the processes of remodeling. The gingival fluid is the medium where changes in the profile and levels of these mediators occur. The aim of this study was to investigate the levels of matrix metalloproteinase-8 and interleukin-1β in gingival fluid samples during the first 3 months of orthodontic treatment with fixed appliances in children. Materials and methods: Twelve children receiving brackets treatment were included in the study; 48 samples of gingival fluid collected from one representative tooth of these children were measured once before placing the brackets, then at 24 hours, at 1 week, and at 3 months. We measured the amount of gingival fluid and the levels of matrix metalloproteinase-8 and interleukin-1β. Filter paper strips were used to collect gingival fluid. After eluting them we made a quantitative analysis of the biomarkers, matrix metalloproteinase-8 and interleukin-1β, using the solid-phase enzyme immunoassay (ELISA). The results showed a slight drop in the levels of both markers compared with baseline values and an increase at three months of orthodontic treatment. A similar tendency was observed in the flow of gingival fluid. Conclusion: Quantitative analysis of matrix metalloproteinase-8 and interleukin-1β in gingival fluid samples is potentially a non-invasive method by which orthodontists can get information about the remodeling processes in the periodontium during orthodontic treatment thus controlling and limiting them within physiological boundaries.
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Penumatsa, Krishna C., Deniz Toksoz, Rod R. Warburton, Mousa Kharnaf, Ioana R. Preston, Navin K. Kapur, Chaitan Khosla, Nicholas S. Hill, and Barry L. Fanburg. "Transglutaminase 2 in pulmonary and cardiac tissue remodeling in experimental pulmonary hypertension." American Journal of Physiology-Lung Cellular and Molecular Physiology 313, no. 5 (November 1, 2017): L752—L762. http://dx.doi.org/10.1152/ajplung.00170.2017.
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Tissue matrix remodeling and fibrosis leading to loss of pulmonary arterial and right ventricular compliance are important features of both experimental and clinical pulmonary hypertension (PH). We have previously reported that transglutaminase 2 (TG2) is involved in PH development while others have shown it to be a cross-linking enzyme that participates in remodeling of extracellular matrix in fibrotic diseases in general. In the present studies, we used a mouse model of experimental PH (Sugen 5416 and hypoxia; SuHypoxia) and cultured primary human cardiac and pulmonary artery adventitial fibroblasts to evaluate the relationship of TG2 to the processes of fibrosis, protein cross-linking, extracellular matrix collagen accumulation, and fibroblast-to-myofibroblast transformation. We report here that TG2 expression and activity as measured by serotonylated fibronectin and protein cross-linking activity along with fibrogenic markers are significantly elevated in lungs and right ventricles of SuHypoxic mice with PH. Similarly, TG2 expression and activity, protein cross-linking activity, and fibrogenic markers are significantly increased in cultured cardiac and pulmonary artery adventitial fibroblasts in response to hypoxia exposure. Pharmacological inhibition of TG2 activity with ERW1041E significantly reduced hypoxia-induced cross-linking activity and synthesis of collagen 1 and α-smooth muscle actin in both the in vivo and in vitro studies. TG2 short interfering RNA had a similar effect in vitro. Our results suggest that TG2 plays an important role in hypoxia-induced pulmonary and right ventricular tissue matrix remodeling in the development of PH.
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Azami, M., M. Anvarinejad, and M. Jamshidian Ghalesefidi. "The important role of matrix metalloproteinases in nematode parasites." Helminthologia 51, no. 3 (September 1, 2014): 167–70. http://dx.doi.org/10.2478/s11687-014-0225-8.
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AbstractMatrix metalloproteinases (MMPs) represent a large family of over twenty different secreted or membrane-bound endopeptidases, involved in many physiological (embryogenesis, precursor or stem cell mobilization, tissue remodeling during wound healing, etc.), as well as pathological (inflammation, tumor progression and metastasis in cancer, vascular pathology, etc.) conditions. For a long time, MMPs were considered only for the ability to degrade extracellular matrix (ECM) molecules (e.g., collagen, laminin, fibronectin) and to release hidden epitopes from the ECM. However, expressions of many MMPs have been associated with several pathological conditions. It has been established that the MMPs are conserved throughout the animal kingdom and studies of invertebrate have demonstrated that primarily they are involved in various developing functions in hydra, Drosophila, sea urchin and nematodes. The syntheses of these proteolytic enzymes and their release as excretory and secretory products have been reported in various parasitic nematodes. Host invasion and tissue migration of several nematodes have been linked to the expression and release of parasite-derived proteases. Studies with enzyme inhibitors suggest that the enzyme may be a metalloproteinase. Moreover, substrate impregnated zymographic analysis of extracts and excretory and secretory products of different nematode parasites have revealed the multiple enzyme activities of MMPs with various molecular weights. More research on MMP degradome in nematode parasites can provide valuable information for intense evaluation of pathogenesis caused by these parasites.
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Stolow, M. A., D. D. Bauzon, J. Li, T. Sedgwick, V. C. Liang, Q. A. Sang, and Y. B. Shi. "Identification and characterization of a novel collagenase in Xenopus laevis: possible roles during frog development." Molecular Biology of the Cell 7, no. 10 (October 1996): 1471–83. http://dx.doi.org/10.1091/mbc.7.10.1471.
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Matrix metalloproteinases (MMPs) participate in extracellular matrix remodeling and degradation and have been implicated in playing important roles during organ development and pathological processes. Although it has been hypothesized for > 30 years that collagenase activities are responsible for collagen degradation during tadpole tail resorption, none of the previously cloned amphibian MMPs have been biochemically demonstrated to be collagenases. Here, we report a novel matrix metalloproteinase gene from metamorphosing Xenopus laevis tadpoles. In vitro biochemical studies demonstrate that this Xenopus enzyme is an interstitial collagenase and has an essentially identical enzymatic activity toward a collagen substrate as the human interstitial collagenase. Sequence comparison of this enzyme to other known MMPs suggests that the Xenopus collagenase is not a homologue of any known collagenases but instead represents a novel collagenase, Xenopus collagenase-4 (xCol4, MMP-18). Interestingly, during development, xCol4 is highly expressed only transiently in whole animals, at approximately the time when tadpole feeding begins, suggesting a role during the maturation of the digestive tract. More importantly, during metamorphosis, xCol4 is regulated in a tissue-dependent manner. High levels of its mRNA are present as the tadpole tail resorbs. Similarly, its expression is elevated during hindlimb morphogenesis and intestinal remodeling. In addition, when premetamorphic tadpoles are treated with thyroid hormone, the causative agent of metamorphosis, xCol4 expression is induced in the tail. These results suggest that xCol4 may facilitate larval tissue degeneration and adult organogenesis during amphibian metamorphosis.
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Sachidanandam, Kamakshi, Vera Portik-Dobos, Aisha I. Kelly-Cobbs, and Adviye Ergul. "Dual endothelin receptor antagonism prevents remodeling of resistance arteries in diabetesThis article is one of a selection of papers published in the two-part special issue entitled 20 Years of Endothelin Research." Canadian Journal of Physiology and Pharmacology 88, no. 6 (June 2010): 616–21. http://dx.doi.org/10.1139/y10-034.
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Vascular remodeling, characterized by extracellular matrix deposition and increased media-to-lumen (M/L) ratio, contributes to the development of microvascular complications in diabetes. We have previously shown in type 2 diabetic Goto–Kakizaki (GK) rats that selective ETA receptor blockade prevents medial thickening of mesenteric arteries via regulation of matrix metalloproteases (MMP), whereas selective ETB receptor blockade augments this thickening. The goal of this study was to determine the effect of combined ETA and ETB receptor blockade on resistance vessel remodeling. Vessel structure, MMP activity, and extracellular matrix proteins were assessed in control Wistar and diabetic GK rats treated with vehicle or bosentan (100 mg/kg per day) for 4 weeks (n = 7–9 per group). Bosentan completely prevented the increase in M/L ratio and MMP-2 activity in diabetes but paradoxically increased M/L ratio and MMP activation in control animals. Collagenase (MMP-13) activity and protein levels were significantly decreased in diabetes. Accordingly, collagen deposition was augmented in GK rats. Dual ET receptor antagonism improved enzyme activity and normalized MMP-13 levels in diabetic animals but blunted MMP-13 activity in control animals. In summary, current findings suggest that diabetes-mediated remodeling of resistance arteries is prevented by dual blockade of ETA and ETB receptors and that the relative role of ET receptors in the regulation of vascular structure differs in the control and disease states.
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Tyagi, Suresh C., and Irving G. Joshua. "Exercise and nutrition in myocardial matrix metabolism, remodeling, regeneration, epigenetics, microcirculation, and muscle." Canadian Journal of Physiology and Pharmacology 92, no. 7 (July 2014): 521–23. http://dx.doi.org/10.1139/cjpp-2014-0197.
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Remodeling and myocardial matrix metabolism contributes to cardiac endothelium–myocyte (perivascular fibrosis), myocyte–myocyte (interstitial fibrosis), and mitochondrion–myocyte (fusion and fission) coupling. Matrix metalloproteinases (MMPs), and tissue inhibitor of metalloproteinases (TIMPs) play differential roles in different tissues and diseases. For example, although present in the heart, MMP-3 is known as stromelysin (i.e., stromal tissue enzyme). Interestingly, TIMP-3 causes apoptosis. Exercise and nutrition are synergistic in the mitigation of diseases: exercise releases exosomes containing miRNAs. Nutrition/vitamins B6 and B12 regulate the metabolism of homocysteine (an epigenetic byproduct of DNA/RNA/protein methylation). Thus, epigenetic silencing is an important therapeutic target. The statistical analysis of cohorts may be less indicative for the treatment of a disease, particularly if the 2 twins are different in terms of responding to the medicine for the same disease, therefore, personalized medicine is the future of therapy.