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Sobota RS, Stucke EM, Coulibaly D, Lawton JG, Cummings BE, Sebastian S, Dara A, Munro JB, Ouattara A, Kone AK, Kane B, Traoré K, Guindo B, Tangara BM, Niangaly A, Ventimiglia NT, Daou M, Diarra I, Tolo Y, Sissoko M, Maiga F, Diawara A, Traore A, Thera A, Laurens MB, Lyke KE, Kouriba B, Doumbo OK, Plowe CV, Goodlett DR, Silva JC, Thera MA, Travassos MA. A shared inflammatory signature across severe malaria syndromes manifested by transcriptomic, proteomic and metabolomic analyses. Nat Commun 2025; 16:4620. [PMID: 40383794 PMCID: PMC12086225 DOI: 10.1038/s41467-025-59281-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Accepted: 04/16/2025] [Indexed: 05/20/2025] Open
Abstract
Factors governing the clinical trajectory of Plasmodium falciparum infection remain an important area of investigation. Here we present transcriptomic, proteomic and metabolomic analyses comparing clinical subtypes of severe Plasmodium falciparum malaria to matched controls with uncomplicated disease in 79 children from Mali. MMP8, IL1R2, and ARG1 transcription is higher across cerebral malaria, severe malarial anemia, and concurrent cerebral malaria and severe malarial anemia, indicating a shared inflammatory signature. Tissue inhibitor of metalloproteinases 1 is the most upregulated protein in cerebral malaria, which along with elevated MMP8 and MMP9 transcription, underscores the importance of the metalloproteinase pathway in central nervous system pathophysiology. L-arginine metabolites are decreased in cerebral malaria, which coupled with increased ARG1 transcription suggests a putative mechanism impairing cerebral vasodilation. Using multi-omics approaches, we thus describe the inflammatory cascade in severe malaria syndromes, and identify potential therapeutic targets and biological markers.
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Affiliation(s)
- Rafal S Sobota
- Malaria Research Program, Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD, USA
- Ken and Ruth Davee Department of Neurology, Northwestern University, Chicago, IL, USA
| | - Emily M Stucke
- Malaria Research Program, Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Drissa Coulibaly
- Malaria Research and Training Center, University of Sciences Techniques and Technologies, Bamako, Mali
| | - Jonathan G Lawton
- Malaria Research Program, Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Bryan E Cummings
- Malaria Research Program, Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Savy Sebastian
- Malaria Research Program, Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Antoine Dara
- Malaria Research and Training Center, University of Sciences Techniques and Technologies, Bamako, Mali
| | - James B Munro
- Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Amed Ouattara
- Malaria Research Program, Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Abdoulaye K Kone
- Malaria Research and Training Center, University of Sciences Techniques and Technologies, Bamako, Mali
| | - Bourama Kane
- Malaria Research and Training Center, University of Sciences Techniques and Technologies, Bamako, Mali
| | - Karim Traoré
- Malaria Research and Training Center, University of Sciences Techniques and Technologies, Bamako, Mali
| | - Bouréima Guindo
- Malaria Research and Training Center, University of Sciences Techniques and Technologies, Bamako, Mali
| | - Bourama M Tangara
- Malaria Research and Training Center, University of Sciences Techniques and Technologies, Bamako, Mali
| | - Amadou Niangaly
- Malaria Research and Training Center, University of Sciences Techniques and Technologies, Bamako, Mali
| | - Noah T Ventimiglia
- Malaria Research Program, Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Modibo Daou
- Malaria Research and Training Center, University of Sciences Techniques and Technologies, Bamako, Mali
| | - Issa Diarra
- Malaria Research and Training Center, University of Sciences Techniques and Technologies, Bamako, Mali
| | - Youssouf Tolo
- Malaria Research and Training Center, University of Sciences Techniques and Technologies, Bamako, Mali
| | - Mody Sissoko
- Malaria Research and Training Center, University of Sciences Techniques and Technologies, Bamako, Mali
| | - Fayçal Maiga
- Malaria Research and Training Center, University of Sciences Techniques and Technologies, Bamako, Mali
| | - Aichatou Diawara
- Malaria Research and Training Center, University of Sciences Techniques and Technologies, Bamako, Mali
| | - Amidou Traore
- Malaria Research and Training Center, University of Sciences Techniques and Technologies, Bamako, Mali
| | - Ali Thera
- Malaria Research and Training Center, University of Sciences Techniques and Technologies, Bamako, Mali
| | - Matthew B Laurens
- Malaria Research Program, Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Kirsten E Lyke
- Malaria Research Program, Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Bourema Kouriba
- Malaria Research and Training Center, University of Sciences Techniques and Technologies, Bamako, Mali
| | - Ogobara K Doumbo
- Malaria Research and Training Center, University of Sciences Techniques and Technologies, Bamako, Mali
| | - Christopher V Plowe
- Malaria Research Program, Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD, USA
| | - David R Goodlett
- Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC, Canada
| | - Joana C Silva
- Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Mahamadou A Thera
- Malaria Research and Training Center, University of Sciences Techniques and Technologies, Bamako, Mali
| | - Mark A Travassos
- Malaria Research Program, Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD, USA.
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Micocci KC, Stotzer US, Moritz MNO. Measuring Matrix Metalloproteinases Activity by Gelatin Zymography. Methods Mol Biol 2025; 2917:65-74. [PMID: 40347332 DOI: 10.1007/978-1-0716-4478-2_6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/12/2025]
Abstract
Gelatin zymography is a widely popular method due to its simplicity, low cost, and quick results, for studying gelatinases in various biological systems. Zymography can detect both the pro and active forms of matrix metalloproteinases MMP-2 (gelatinase A) and MMP-9 (gelatinase B). These MMPs play critical roles in the pathophysiology of many human diseases, particularly in cancer progression. Gelatin zymography is a method based on a suitable protein substrate incorporated into a sodium dodecyl sulfate-polyacrylamide gel. Substrate degradation by protease-containing samples can be visualized through the contrast between the Coomassie blue-stained gel and the white band of substrate degradation. Here, we provide a straightforward, step-by-step methodology for detecting MMP-2 and MMP-9 gelatinases in tumor cells. It is essential to highlight that accurately interpreting the data requires a thorough understanding of the technique's principles.
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Affiliation(s)
- Kelli C Micocci
- Department of Chemistry, Federal University of São Carlos, Sao Paulo, Brazil
| | - Uliana S Stotzer
- Human Movement Sciences Research Group, Methodist University of Piracicaba, Sao Paulo, Brazil
| | - Milene N O Moritz
- Sao Carlos Institute of Chemistry, University of Sao Paulo, Sao Paulo, Brazil
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Giri SS, Tripathi AS, Erkekoğlu P, Zaki MEA. Molecular pathway of pancreatic cancer-associated neuropathic pain. J Biochem Mol Toxicol 2024; 38:e23638. [PMID: 38613466 DOI: 10.1002/jbt.23638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Revised: 11/29/2023] [Accepted: 12/21/2023] [Indexed: 04/15/2024]
Abstract
The pancreas is a heterocrine gland that has both exocrine and endocrine parts. Most pancreatic cancer begins in the cells that line the ducts of the pancreas and is called pancreatic ductal adenocarcinoma (PDAC). PDAC is the most encountered pancreatic cancer type. One of the most important characteristic features of PDAC is neuropathy which is primarily due to perineural invasion (PNI). PNI develops tumor microenvironment which includes overexpression of fibroblasts cells, macrophages, as well as angiogenesis which can be responsible for neuropathy pain. In tumor microenvironment inactive fibroblasts are converted into an active form that is cancer-associated fibroblasts (CAFs). Neurotrophins they also increase the level of Substance P, calcitonin gene-related peptide which is also involved in pain. Matrix metalloproteases are the zinc-associated proteases enzymes which activates proinflammatory interleukin-1β into its activated form and are responsible for release and activation of Substance P which is responsible for neuropathic pain by transmitting pain signal via dorsal root ganglion. All the molecules and their role in being responsible for neuropathic pain are described below.
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Affiliation(s)
| | - Alok Shiomurti Tripathi
- Department of Pharmacology, Era College of Pharmacy, Era University, Lucknow, Uttar Pradesh, India
| | - Pınar Erkekoğlu
- Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Hacettepe University, Ankara, Turkey
| | - Magdi E A Zaki
- Department of Chemistry, Faculty of Science, Imam Mohammad lbn Saud Islamic University, Riyadh, Saudi Arabia
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Dai XY, Liu L, Song FH, Gao SJ, Wu JY, Li DY, Zhang LQ, Liu DQ, Zhou YQ, Mei W. Matrix metalloproteinases as attractive therapeutic targets for chronic pain: A narrative review. Int J Biol Macromol 2024; 261:129619. [PMID: 38272407 DOI: 10.1016/j.ijbiomac.2024.129619] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Revised: 01/08/2024] [Accepted: 01/18/2024] [Indexed: 01/27/2024]
Abstract
Chronic pain constitutes an abnormal pain state that detrimentally affects the quality of life, daily activities, occupational performance, and stability of mood. Despite the prevalence of chronic pain, effective drugs with potent abirritation and minimal side effects remain elusive. Substantial studies have revealed aberrant activation of the matrix metalloproteinases (MMPs) in multiple chronic pain models. Additionally, emerging evidence has demonstrated that the downregulation of MMPs can alleviate chronic pain in diverse animal models, underscoring the unique and crucial role of MMPs in different stages and types of chronic pain. This review delves into the mechanistic insights and roles of MMPs in modulating chronic pain. The aberrant activation of MMPs has been linked to neuropathic pain through mechanisms involving myelin abnormalities in peripheral nerve and spinal dorsal horn (SDH), hyperexcitability of dorsal root ganglion (DRG) neurons, activation of N-methyl-d-aspartate receptors (NMDAR) and Ca2+-dependent signals, glial cell activation, and proinflammatory cytokines release. Different MMPs also contribute significantly to inflammatory pain and cancer pain. Furthermore, we summarized the substantial therapeutic potential of MMP pharmacological inhibitors across different types of chronic pain. Overall, our findings underscore the promising therapeutic prospects of MMPs targeting for managing chronic pain.
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Affiliation(s)
- Xin-Yi Dai
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, Wuhan, China; Wuhan Clinical Research Center for Geriatric Anesthesia, Wuhan, China
| | - Lin Liu
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, Wuhan, China; Wuhan Clinical Research Center for Geriatric Anesthesia, Wuhan, China
| | - Fan-He Song
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, Wuhan, China; Wuhan Clinical Research Center for Geriatric Anesthesia, Wuhan, China
| | - Shao-Jie Gao
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, Wuhan, China; Wuhan Clinical Research Center for Geriatric Anesthesia, Wuhan, China
| | - Jia-Yi Wu
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, Wuhan, China; Wuhan Clinical Research Center for Geriatric Anesthesia, Wuhan, China
| | - Dan-Yang Li
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, Wuhan, China; Wuhan Clinical Research Center for Geriatric Anesthesia, Wuhan, China
| | - Long-Qing Zhang
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, Wuhan, China; Wuhan Clinical Research Center for Geriatric Anesthesia, Wuhan, China
| | - Dai-Qiang Liu
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, Wuhan, China; Wuhan Clinical Research Center for Geriatric Anesthesia, Wuhan, China
| | - Ya-Qun Zhou
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, Wuhan, China; Wuhan Clinical Research Center for Geriatric Anesthesia, Wuhan, China.
| | - Wei Mei
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, Wuhan, China; Wuhan Clinical Research Center for Geriatric Anesthesia, Wuhan, China.
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Regulation of Tumor Metabolism and Extracellular Acidosis by the TIMP-10-CD63 Axis in Breast Carcinoma. Cells 2021; 10:cells10102721. [PMID: 34685701 PMCID: PMC8535136 DOI: 10.3390/cells10102721] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 10/05/2021] [Accepted: 10/07/2021] [Indexed: 12/24/2022] Open
Abstract
A hallmark of malignant solid tumor is extracellular acidification coupled with metabolic switch to aerobic glycolysis. Using the human MCF10A progression model of breast cancer, we show that glycolytic switch and extracellular acidosis in aggressive cancer cells correlate with increased expression of tissue inhibitor of metalloproteinase-1 (TIMP-1), known to induce intracellular signal transduction through the interaction with its cell surface receptor CD63, independent of its metalloproteinase inhibitory function. We found that, in aggressive breast carcinoma, the TIMP-1–CD63 signaling axis induced a metabolic switch by upregulating the rate of aerobic glycolysis, lowering mitochondrial respiration, preventing intracellular acidification, and inducing extracellular acidosis. Carbonic anhydrase IX (CAIX), a regulator of cellular pH through the hydration of metabolically released pericellular CO2, was identified as a downstream mediator of the TIMP-1–CD63 signaling axis responsible for extracellular acidosis. Consistently with our previous study, the TIMP-1–CD63 signaling promoted survival of breast cancer cells. Interestingly, breast carcinoma cell survival was drastically reduced upon shRNA-mediated knockdown of CAIX expression, demonstrating the significance of CAIX-regulated pH in the TIMP-1–CD63-mediated cancer cell survival. Taken together, the present study demonstrates the functional significance of TIMP-1–CD63–CAXI signaling axis in the regulation of tumor metabolism, extracellular acidosis, and survival of breast carcinoma. We propose that this axis may serve as a novel therapeutic target.
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Marônek M, Marafini I, Gardlík R, Link R, Troncone E, Monteleone G. Metalloproteinases in Inflammatory Bowel Diseases. J Inflamm Res 2021; 14:1029-1041. [PMID: 33790618 PMCID: PMC8001665 DOI: 10.2147/jir.s288280] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Accepted: 03/09/2021] [Indexed: 12/13/2022] Open
Abstract
Inflammatory bowel diseases (IBD) are chronic inflammatory diseases of the gastrointestinal tract, encompassing two main disorders: Crohn's disease (CD) and ulcerative colitis (UC). In both these pathologies, excessive and local immune response against luminal antigens promotes a pathological process leading to various degrees of gut damage. Matrix metalloproteinases (MMPs) are a family of neutral proteases with the ability to degrade all components of extracellular matrix. In physiological conditions, MMPs are produced at very low level and generally in the latent form and are involved in the normal tissue turnover. Their function is inhibited by tissue inhibitors of metalloproteinases (TIMPs). However, in inflamed tissue of IBD patients, MMPs are produced in excess and/or the activity of TIMPs is not sufficient to block MMPs, thereby making a major contribution to the IBD-related mucosal degradation. In this review, we summarize the available evidence on the expression and role of MMPs in IBD.
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Affiliation(s)
- Martin Marônek
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University in Bratislava, Bratislava, 81108, Slovakia
| | - Irene Marafini
- Department of Systems Medicine, University of Rome "Tor Vergata", Rome, 00133, Italy
| | - Roman Gardlík
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University in Bratislava, Bratislava, 81108, Slovakia
| | - René Link
- Institute of Experimental Medicine, Faculty of Medicine, University of Pavol Jozef Šafárik, Košice, 040 11, Slovakia
| | - Edoardo Troncone
- Department of Systems Medicine, University of Rome "Tor Vergata", Rome, 00133, Italy
| | - Giovanni Monteleone
- Department of Systems Medicine, University of Rome "Tor Vergata", Rome, 00133, Italy
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Zhang JF, Wang GL, Zhou ZJ, Fang XQ, Chen S, Fan SW. Expression of Matrix Metalloproteinases, Tissue Inhibitors of Metalloproteinases, and Interleukins in Vertebral Cartilage Endplate. Orthop Surg 2018; 10:306-311. [PMID: 30474324 DOI: 10.1111/os.12409] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2017] [Accepted: 10/30/2017] [Indexed: 12/19/2022] Open
Abstract
OBJECTIVE Turnover of cartilage endplate extracellular matrix (ECM) may play an important role in disc degeneration and low back pain (LBP). However, the expression pattern of pro-inflammatory factors, matrix metalloproteinases (MMP), and tissue inhibitors of metalloproteinases (TIMP) in the cartilage endplates (CEP) of intervertebral discs (IVD) is not understood. We aimed to examine the transcriptional levels of MMP, TIMP, and interleukins (IL), and the correlations between them. METHODS Thirty degenerated cartilage endplate samples from patients with LBP who underwent lumbar fusion surgery were included in the degenerated group. Ten patients without LBP history who underwent lumbar surgery because of vertebral burst fractures were included in the control group. The degenerative severity of the samples was evaluated by MRI, and hematoxylin-eosin and safranin O-fast green (SO-FG) staining. Real-time polymerase chain reaction (RT-PCR) was used to detect the mRNA levels of MMP-1, MMP-3, MMP-9, MMP-13, TIMP-1, TIMP-2, TIMP-3, IL-1α, IL-1β, and IL-6. The correlations between the levels of these genes were tested using Spearman's rho test. RESULTS Hematoxylin-eosin and SO-FG staining confirmed a decrease in cell number and proteoglycans in the degenerated cartilage endplate. MRI showed significant signal changes in degenerated cartilage endplates. Patients in the degenerated group showed a higher rate of endplate Modic changes when compared with the control group. MMP-3, MMP-9, TIMP-3, IL-1α, and IL-1β were elevated with statistical significance, while MMP-1, MMP-13, TIMP-1, TIMP-2, and IL-6 were changed without statistical significance or remained unchanged. Expression of MMP-3 was positively correlated with IL-1α (Spearman coefficient, 0.486; P < 0.05); expression of TIMP-3 was positively correlated with MMP-9, IL-1α, and IL-1β (Spearman coefficient, 0.577, 0.407, and 0.571, respectively; P < 0.05). CONCLUSION MMP-3, MMP-9, TIMP-3, IL-1α, and IL-1β may play a role in the process of cartilage endplate degeneration. MMP-3 may be regulated by IL-1α, and TIMP-3 might be associated with MMP-9 and regulated by IL-1α and IL-1β.
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Affiliation(s)
- Jian-Feng Zhang
- Department of Orthopaedics, Sir Run Run Shaw Hospital, Medical College of Zhejiang University, Hangzhou, China
| | - Gang-Liang Wang
- Department of Orthopaedics, Sir Run Run Shaw Hospital, Medical College of Zhejiang University, Hangzhou, China
| | - Zhi-Jie Zhou
- Department of Orthopaedics, Sir Run Run Shaw Hospital, Medical College of Zhejiang University, Hangzhou, China
| | - Xiang-Qian Fang
- Department of Orthopaedics, Sir Run Run Shaw Hospital, Medical College of Zhejiang University, Hangzhou, China
| | - Shuai Chen
- Department of Orthopaedics, Sir Run Run Shaw Hospital, Medical College of Zhejiang University, Hangzhou, China
| | - Shun-Wu Fan
- Department of Orthopaedics, Sir Run Run Shaw Hospital, Medical College of Zhejiang University, Hangzhou, China
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The hippocampal extracellular matrix regulates pain and memory after injury. Mol Psychiatry 2018; 23:2302-2313. [PMID: 30254235 PMCID: PMC6294737 DOI: 10.1038/s41380-018-0209-z] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2018] [Revised: 05/26/2018] [Accepted: 06/18/2018] [Indexed: 12/11/2022]
Abstract
Chronic pain poses a heavy burden for the individual and society, comprising personal suffering, comorbid psychiatric symptoms, cognitive decline, and disability. Treatment options are poor due in large part to pain centralization, where an initial injury can result in lasting CNS maladaptations. Hippocampal cellular plasticity in chronic pain has become a focus of study due to its roles in cognition, memory, and the experience of pain itself. However, the extracellular alterations that parallel and facilitate changes in hippocampal function have not been addressed to date. Here we show structural and biochemical plasticity in the hippocampal extracellular matrix (ECM) that is linked to behavioral, cellular, and synaptic changes in a mouse model of chronic pain. Specifically, we report deficits in working location memory that are associated with decreased hippocampal dendritic complexity, altered ECM microarchitecture, decreased ECM rigidity, and changes in the levels of key ECM components and enzymes, including increased levels of MMP8. We also report aberrations in long-term potentiation (LTP) and a loss of inhibitory interneuron perineuronal ECM nets, potentially accounting for the aberrations in LTP. Finally, we demonstrate that MMP8 is upregulated after injury and that its genetic downregulation normalizes the behavioral, electrophysiological, and extracellular alterations. By linking specific extracellular changes to the chronic pain phenotype, we provide a novel mechanistic understanding of pain centralization that provides new targets for the treatment of chronic pain.
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Ameliorating effects of Raphanus sativus leaves on sodium arsenite-induced perturbation of blood indices in Swiss albino mice. Asian Pac J Trop Biomed 2017. [DOI: 10.1016/j.apjtb.2017.09.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
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Wen H, Qin Y, Zhong W, Li C, Liu X, Shen Y. Trivalent metal ions based on inorganic compounds with in vitro inhibitory activity of matrix metalloproteinase 13. Enzyme Microb Technol 2016; 92:9-17. [PMID: 27542739 DOI: 10.1016/j.enzmictec.2016.06.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2016] [Revised: 06/07/2016] [Accepted: 06/10/2016] [Indexed: 02/02/2023]
Abstract
Collagenase-3 (MMP-13) inhibitors have attracted considerable attention in recent years and have been developed as a therapeutic target for a variety of diseases, including cancer. Matrix metalloproteinases (MMPs) can be inhibited by a multitude of compounds, including hydroxamic acids. Studies have shown that materials and compounds containing trivalent metal ions, particularly potassium hexacyanoferrate (III) (K3[Fe(CN)6]), exhibit cdMMP-13 inhibitory potential with a half maximal inhibitory concentration (IC50) of 1.3μM. The target protein was obtained by refolding the recombinant histidine-tagged cdMMP-13 using size exclusion chromatography (SEC). The secondary structures of the refolded cdMMP-13 with or without metal ions were further analyzed via circular dichroism and the results indicate that upon binding with metal ions, an altered structure with increased domain stability was obtained. Furthermore, isothermal titration calorimetry (ITC) experiments demonstrated that K3[Fe(CN)6]is able to bind to MMP-13 and endothelial cell tube formation tests provide further evidence for this interaction to exhibit anti-angiogenesis potential. To the best of our knowledge, no previous report of an inorganic compound featuring a MMP-13 inhibitory activity has ever been reported in the literature. Our results demonstrate that K3[Fe(CN)6] is useful as a new effective and specific inhibitor for cdMMP-13 which may be of great potential for future drug screening applications.
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Affiliation(s)
- Hanyu Wen
- Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, College of Chemistry and Materials Science, Northwest University, Shaanxi Alcohol Ether and Biomass Energy Engineering Research Center, Key laboratory of Yulin Desert Plants Resources, 229 Taibai North Road, Xi'an 710069, PR China
| | - Yuan Qin
- College of Pharmacy, Nankai University, PR China
| | | | - Cong Li
- Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, College of Chemistry and Materials Science, Northwest University, Shaanxi Alcohol Ether and Biomass Energy Engineering Research Center, Key laboratory of Yulin Desert Plants Resources, 229 Taibai North Road, Xi'an 710069, PR China
| | - Xiang Liu
- Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, College of Chemistry and Materials Science, Northwest University, Shaanxi Alcohol Ether and Biomass Energy Engineering Research Center, Key laboratory of Yulin Desert Plants Resources, 229 Taibai North Road, Xi'an 710069, PR China; College of Pharmacy, Nankai University, PR China.
| | - Yehua Shen
- Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, College of Chemistry and Materials Science, Northwest University, Shaanxi Alcohol Ether and Biomass Energy Engineering Research Center, Key laboratory of Yulin Desert Plants Resources, 229 Taibai North Road, Xi'an 710069, PR China; College of Pharmacy, Nankai University, PR China.
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Geng J, Huang C, Jiang S. Roles and regulation of the matrix metalloproteinase system in parturition. Mol Reprod Dev 2016; 83:276-86. [PMID: 26888468 DOI: 10.1002/mrd.22626] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2015] [Accepted: 02/10/2016] [Indexed: 12/23/2022]
Abstract
Significant tissue destruction, repair, and remodeling are involved in parturition, which involves fetal membrane rupture, cervical ripening, and uterine contraction and its subsequent involution. Extracellular matrix degradation and remodeling by proteolytic enzymes, such as matrix metalloproteinases (MMPs), are required for the final steps of parturition. MMPs participate in physiological degradation and remodeling through their proteolytic activities on specific substrates, and are balanced by the action of their inhibitors. Disruption to this balance can result in pathological stress that ends with preterm or post-term birth or pre-eclampsia. In this review, we examine the roles and regulation of the MMP system in physiological and pathological labor, and propose a model that illustrates the mechanisms by which the MMP system contributes to these processes.
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Affiliation(s)
- Junnan Geng
- Key Laboratory of Swine Genetics and Breeding of Agricultural Ministry, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China.,The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China
| | - Cong Huang
- Key Laboratory of Swine Genetics and Breeding of Agricultural Ministry, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China.,The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China
| | - Siwen Jiang
- Key Laboratory of Swine Genetics and Breeding of Agricultural Ministry, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China.,The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China
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Islam MS, Mohanto NC, Karim MR, Aktar S, Hoque MM, Rahman A, Jahan M, Khatun R, Aziz A, Salam KA, Saud ZA, Hossain M, Rahman A, Mandal A, Haque A, Miyataka H, Himeno S, Hossain K. Elevated concentrations of serum matrix metalloproteinase-2 and -9 and their associations with circulating markers of cardiovascular diseases in chronic arsenic-exposed individuals. Environ Health 2015; 14:92. [PMID: 26637202 PMCID: PMC4670511 DOI: 10.1186/s12940-015-0079-7] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2015] [Accepted: 11/26/2015] [Indexed: 05/21/2023]
Abstract
BACKGROUND Cardiovascular diseases (CVDs) and cancers are the major causes of chronic arsenic exposure-related morbidity and mortality. Matrix metalloproteinase-2 (MMP-2) and -9 (MMP-9) are deeply involved in the pathogenesis of CVDs and cancers. This study has been designed to evaluate the interactions of arsenic exposure with serum MMP-2 and MMP-9 concentrations especially in relation to the circulating biomarkers of CVDs. METHODS A total of 373 human subjects, 265 from arsenic-endemic and 108 from non-endemic areas in Bangladesh were recruited for this study. Arsenic concentrations in the specimens were measured by inductively coupled plasma mass spectroscopy (ICP-MS) and serum MMPs were quantified by immunoassay kits. RESULTS Serum MMP-2 and MMP-9 concentrations in arsenic-endemic population were significantly (p < 0.001) higher than those in non-endemic population. Both MMPs showed significant positive interactions with drinking water (r s = 0.208, p < 0.001 for MMP-2; r s = 0.163, p < 0.01 for MMP-9), hair (r s = 0.163, p < 0.01 for MMP-2; r s = 0.173, p < 0.01 for MMP-9) and nail (r s = 0.160, p < 0.01 for MMP-2; r s = 0.182, p < 0.001 for MMP-9) arsenic of the study subjects. MMP-2 concentrations were 1.02, 1.03 and 1.05 times, and MMP-9 concentrations were 1.03, 1.06 and 1.07 times greater for 1 unit increase in log-transformed water, hair and nail arsenic concentrations, respectively, after adjusting for covariates (age, sex, BMI, smoking habit and hypertension). Furthermore, both MMPs were increased dose-dependently when the study subjects were split into three (≤10, 10.1-50 and > 50 μg/L) groups based on the regulatory upper limit of water arsenic concentration set by WHO and Bangladesh Government. MMPs were also found to be significantly (p < 0.05) associated with each other. Finally, the concentrations of both MMPs were correlated with several circulating markers related to CVDs. CONCLUSIONS This study showed the significant positive associations and dose-response relationships of arsenic exposure with serum MMP-2 and MMP-9 concentrations. This study also showed the interactions of MMP-2 and MMP-9 concentrations with the circulating markers of CVDs suggesting the MMP-2 and MMP-9 -mediated mechanism of arsenic-induced CVDs.
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Affiliation(s)
- Md Shofikul Islam
- Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi-6205, Bangladesh
- Department of Applied Nutrition and Food Technology, Islamic University, Kushtia-7003, Bangladesh
| | - Nayan Chandra Mohanto
- Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi-6205, Bangladesh
| | - Md Rezaul Karim
- Department of Applied Nutrition and Food Technology, Islamic University, Kushtia-7003, Bangladesh
| | - Sharmin Aktar
- Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi-6205, Bangladesh
| | - Md Mominul Hoque
- Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi-6205, Bangladesh
| | - Atiqur Rahman
- Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi-6205, Bangladesh
| | - Momotaj Jahan
- Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi-6205, Bangladesh
| | - Rabeya Khatun
- Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi-6205, Bangladesh
| | - Abdul Aziz
- Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi-6205, Bangladesh
| | - Kazi Abdus Salam
- Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi-6205, Bangladesh
- Infectious Disease and Immunogenetics Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Zahangir Alam Saud
- Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi-6205, Bangladesh
| | | | - Aminur Rahman
- Systems Biology Research Centre, School of Bioscience, University of Skövde, Skövde, Sweden
| | - Abul Mandal
- Systems Biology Research Centre, School of Bioscience, University of Skövde, Skövde, Sweden
| | - Azizul Haque
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA
| | - Hideki Miyataka
- Laboratory of Molecular Nutrition and Toxicology, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima 770-8514, Japan
| | - Seiichiro Himeno
- Laboratory of Molecular Nutrition and Toxicology, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima 770-8514, Japan
| | - Khaled Hossain
- Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi-6205, Bangladesh.
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Olivas-Calderón E, Recio-Vega R, Gandolfi AJ, Lantz RC, González-Cortes T, Gonzalez-De Alba C, Froines JR, Espinosa-Fematt JA. Lung inflammation biomarkers and lung function in children chronically exposed to arsenic. Toxicol Appl Pharmacol 2015; 287:161-167. [PMID: 26048584 PMCID: PMC4751871 DOI: 10.1016/j.taap.2015.06.001] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2015] [Revised: 05/28/2015] [Accepted: 06/01/2015] [Indexed: 01/11/2023]
Abstract
Evidence suggests that exposure to arsenic in drinking water during early childhood or in utero has been associated with an increase in respiratory symptoms or diseases in the adulthood, however only a few studies have been carried out during those sensitive windows of exposure. Recently our group demonstrated that the exposure to arsenic during early childhood or in utero in children was associated with impairment in the lung function and suggested that this adverse effect could be due to a chronic inflammation response to the metalloid. Therefore, we designed this cross-sectional study in a cohort of children associating lung inflammatory biomarkers and lung function with urinary As levels. A total of 275 healthy children were partitioned into four study groups according with their arsenic urinary levels. Inflammation biomarkers were measured in sputum by ELISA and the lung function was evaluated by spirometry. Fifty eight percent of the studied children were found to have a restrictive spirometric pattern. In the two highest exposed groups, the soluble receptor for advanced glycation end products' (sRAGE) sputum level was significantly lower and matrix metalloproteinase-9 (MMP-9) concentration was higher. When the biomarkers were correlated to the urinary arsenic species, negative associations were found between dimethylarsinic (DMA), monomethylarsonic percentage (%MMA) and dimethylarsinic percentage (%DMA) with sRAGE and positive associations between %DMA with MMP-9 and with the MMP-9/tissue inhibitor of metalloproteinase (TIMP-1) ratio. In conclusion, chronic arsenic exposure of children negatively correlates with sRAGE, and positively correlated with MMP-9 and MMP-9/TIMP-1 levels, and increases the frequency of an abnormal spirometric pattern. Arsenic-induced alterations in inflammatory biomarkers may contribute to the development of restrictive lung diseases.
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Affiliation(s)
- Edgar Olivas-Calderón
- Department of Environmental Health, Biomedical Research Center, School of Medicine, University of Coahuila, Torreon, Coahuila, Mexico; School of Medicine, University Juarez of Durango, Gomez Palacio, Durango, Mexico.
| | - Rogelio Recio-Vega
- Department of Environmental Health, Biomedical Research Center, School of Medicine, University of Coahuila, Torreon, Coahuila, Mexico.
| | - A Jay Gandolfi
- Southwest Environmental Health Science Center, University of Arizona, Tucson, AZ, USA; Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ, USA.
| | - R Clark Lantz
- Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ, USA; Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ, USA.
| | - Tania González-Cortes
- Department of Environmental Health, Biomedical Research Center, School of Medicine, University of Coahuila, Torreon, Coahuila, Mexico.
| | - Cesar Gonzalez-De Alba
- Department of Environmental Health, Biomedical Research Center, School of Medicine, University of Coahuila, Torreon, Coahuila, Mexico.
| | - John R Froines
- Center for Environmental and Occupational Health, School of Public Health, University of California at Los Angeles, Los Angeles, CA, USA.
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Yang HK, Jeong KC, Kim YK, Jung ST. Role of matrix metalloproteinase (MMP) 2 and MMP-9 in soft tissue sarcoma. Clin Orthop Surg 2014; 6:443-54. [PMID: 25436070 PMCID: PMC4233225 DOI: 10.4055/cios.2014.6.4.443] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2013] [Accepted: 03/11/2014] [Indexed: 01/22/2023] Open
Abstract
Background We investigated the expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in malignant fibrous histiocytoma (MFH), and determined whether these could be useful as prognostic factors. Methods Among patients treated from 1993 to 2007, 30 cases of MFH were evaluated. Immunohistochemical staining was performed for MMP-2, MMP-9, TIMP-1, and TIMP-2 using paraffin wax-embedded blocks of MFH tissues. Reverse transcriptase polymerase chain reaction (RT-PCR) and Western blot and zymography were performed using fresh tissues obtained from 17 of the 30 cases. The levels of MMP and TIMP expression were compared between the MFH and normal control groups, and between non-metastatic and metastatic MFH groups. Results Expression levels of MMP-2, MMP-9, TIMP-1, and TIMP-2 were higher in the MFH group than the control group by RT-PCR, Western blotting, and zymography. Immunohistochemical staining revealed that MMP-2 and MMP-9 protein expression was higher in the metastatic than in the non-metastatic group. The expression levels of MMP-2 and TIMP-1 were significantly higher in the metastatic than in the non-metastatic group (p < 0.05) by RT-PCR. By Western blot analysis, the expression levels of MMP-2, TIMP-1, and TIMP-2 were higher in the metastatic group (p < 0.05), but MMP-9 showed only a slight increase in the metastatic group compared with the non-metastatic group (p > 0.05). Finally, gelatin zymography analysis showed that the expression levels of the pro- and active forms of MMP-2 were significantly higher in the metastatic group (p < 0.05), but the expression of the pro- and active forms of MMP-9 showed a slight decrease in the metastatic group (p > 0.05). Conclusions These results suggest that MMP-2, MMP-9, TIMP-1, and TIMP-2 may have important roles in the development and progression of MFH, and that the degree of expression of these metalloproteinases and their inhibitors, especially MMP-2, could be useful as prognostic factors related to metastasis in MFH.
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Affiliation(s)
- Hyun Kee Yang
- Department of Orthopaedic Surgery, Chonnam National University Medical School, Gwangju, Korea
| | - Kwang Cheul Jeong
- Department of Orthopaedic Surgery, Chonnam National University Medical School, Gwangju, Korea
| | - Yang Kyung Kim
- Department of Orthopaedic Surgery, Chonnam National University Medical School, Gwangju, Korea
| | - Sung Taek Jung
- Department of Orthopaedic Surgery, Chonnam National University Medical School, Gwangju, Korea
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Maślanka T. Pharmacology of topical prostaglandin F2 α analogs and their place in the treatment of glaucoma in small animals. J Vet Pharmacol Ther 2014; 38:105-12. [PMID: 25230091 DOI: 10.1111/jvp.12161] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2013] [Accepted: 08/04/2014] [Indexed: 02/05/2023]
Abstract
A distinguishing feature of the most common types of glaucoma is an increased intra-ocular pressure (IOP), which has a damaging effect on optic nerve axons, leading to the progressive loss of retinal ganglion cells. Therefore, IOP-lowering medications are the mainstay of glaucoma therapy. Topical prostaglandin F2 α analogs (PGAs) are a relatively new class of ocular hypotensive drugs, which have made a huge impact on the treatment of glaucoma in dogs. This study summarizes the current state of knowledge on the mechanism of action of these agents and their effect on IOP in dogs and cats. It also discusses potential harmful side effects of PGAs and presents contemporary opinions about their role and place in the medical management of glaucoma in small animals.
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Affiliation(s)
- T Maślanka
- Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, University of Warmia and Mazury, Olsztyn, Poland
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16
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Lenglet S, Montecucco F, Mach F, Schaller K, Gasche Y, Copin JC. Analysis of the expression of nine secreted matrix metalloproteinases and their endogenous inhibitors in the brain of mice subjected to ischaemic stroke. Thromb Haemost 2014; 112:363-378. [PMID: 24671655 DOI: 10.1160/th14-01-0007] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2014] [Accepted: 02/20/2014] [Indexed: 12/18/2022]
Abstract
Matrix metalloproteinases (MMPs) are a family of more than twenty secreted and cell-surface endopeptidases. Among them, MMP2, MMP3 and MMP9 are involved in blood-brain barrier injury and neuronal death after cerebral ischaemia. On the other hand, very little is known about the expression of the other secreted MMPs. Herein, we compared the global changes in MMP1, MMP2, MMP3, MMP7, MMP8, MMP9, MMP10, MMP12 and MMP13, and their endogenous inhibitors TIMP1 and TIMP2, both at the mRNA and protein levels, during the hyperacute (6 h), acute (24 h) and subacute (72 h) stages following transient focal cerebral ischaemia and treatment with recombinant tissue plasminogen activator (rtPA). We observed a significant increase in MMP1, MMP2, MMP9, MMP10, MMP13 and TIMP1 levels during the acute stage of reperfusion, which was further amplified during the subacute stage for MMP1, MMP2, MMP10 and TIMP1. In general, no change of MMP3, MMP7, MMP8, MMP12 and TIMP2 was observed. However, rtPA treatment induced a rapid increase in MMP1/TIMP2, MMP2/TIMP2, MMP8/TIMP2 and MMP9/TIMP2 ratios during the hyperacute stage of reperfusion compared to saline treatment, which may have potential implications in the early disruption of the blood-brain barrier after rtPA treatment.
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Affiliation(s)
| | | | | | | | | | - J-C Copin
- Jean-Christophe Copin, Division of Cardiology, Fondation for Medical Researches, Avenue de la Roseraie 64, 1205 Geneva, Switzerland, E-mail: ;
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17
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Esteso G, Luzón E, Sarmiento E, Gómez-Caro R, Steinle A, Murphy G, Carbone J, Valés-Gómez M, Reyburn HT. Altered microRNA expression after infection with human cytomegalovirus leads to TIMP3 downregulation and increased shedding of metalloprotease substrates, including MICA. THE JOURNAL OF IMMUNOLOGY 2014; 193:1344-52. [PMID: 24973455 DOI: 10.4049/jimmunol.1303441] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Proteolytic shedding of ligands for the NK group 2D (NKG2D) receptor is a strategy used by tumors to modulate immune recognition by NK cells and cytotoxic T cells. A number of metalloproteases, especially those of the A disintegrin and metalloprotease (ADAM) family, can mediate NKG2D ligand cleavage and this process can be modulated by expression of the thiol isomerase ERp5. In this article, we describe that an increased shedding of the NKG2D ligand MICA is observed postinfection with several strains of human CMV due to an enhanced activity of ADAM17 (TNF-α converting enzyme) and matrix metalloprotease 14 caused by a reduction in the expression of the endogenous inhibitor of metalloproteases tissue inhibitors of metalloproteinase 3 (TIMP3). This decrease in TIMP3 expression correlates with increased expression of a cellular miRNA known to target TIMP3, and we also identify a human CMV-encoded microRNA able to modulate TIMP3 expression. These observations characterize a novel viral strategy to influence the shedding of cell-surface molecules involved in immune response modulation. They also provide an explanation for previous reports of increased levels of various ADAM17 substrates in the serum from patients with CMV disease. Consistent with this hypothesis, we detected soluble MICA in serum of transplant recipients with CMV disease. Finally, these data suggest that it might be worthwhile to prospectively study ADAM17 activity in a larger group of patients to assay whether this might be a useful biomarker to identify patients at risk for development of CMV disease.
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Affiliation(s)
- Gloria Esteso
- Department of Immunology and Oncology, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Científicas, Madrid 28049, Spain
| | - Elisa Luzón
- Department of Immunology and Oncology, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Científicas, Madrid 28049, Spain
| | - Elisabeth Sarmiento
- Transplant Immunology Group, Clinical Immunology Department, University Hospital Gregorio Marañón, 28007 Madrid, Spain
| | - Ruth Gómez-Caro
- Department of Immunology and Oncology, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Científicas, Madrid 28049, Spain
| | - Alexander Steinle
- Institute for Molecular Medicine, Goethe-University, D-60590 Frankfurt am Main, Germany; and
| | - Gillian Murphy
- Department of Oncology, University of Cambridge, Cancer Research United Kingdom, Cambridge Research Institute, Li Ka Shing Centre, Cambridge CB2 0RE, United Kingdom
| | - Javier Carbone
- Transplant Immunology Group, Clinical Immunology Department, University Hospital Gregorio Marañón, 28007 Madrid, Spain
| | - Mar Valés-Gómez
- Department of Immunology and Oncology, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Científicas, Madrid 28049, Spain
| | - Hugh T Reyburn
- Department of Immunology and Oncology, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Científicas, Madrid 28049, Spain;
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Uchida C, Haas TL. Endothelial cell TIMP-1 is upregulated by shear stress via Sp-1 and the TGFβ1 signaling pathways. Biochem Cell Biol 2013; 92:77-83. [PMID: 24471921 DOI: 10.1139/bcb-2013-0086] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Laminar shear stress promotes vascular integrity by inhibiting proteolysis of the extracellular matrix (ECM) surrounding the microvasculature. We hypothesized that the matrix metalloproteinase inhibitor TIMP-1 would be upregulated in endothelial cells exposed to shear stress. Microvascular endothelial cells isolated from rat or mouse skeletal muscles were exposed to laminar shear stress for 2, 4, or 24 h. A biphasic increase in TIMP-1 protein was observed at 2 and 24 h of shear stress exposure. Sp-1 siRNA prevented the increase in TIMP-1 after 2, but not 24, hours of shear exposure. TGFβ production and Smad2/3 phosphorylation are increased by shear stress. Inhibition of TGFβ signaling, either by use of the TGFβ receptor 1 inhibitor SB-431542 or with Smad 2/3 siRNA, abrogated the shear stress-induced increase in TIMP-1 mRNA after 24 h of shear stress exposure. These results suggest that both acute and chronic elevated laminar shear stress act to maintain vessel integrity through increasing TIMP-1 production, but that the TGFβ signaling pathway is essential to maintain TIMP-1 expression during chronic shear stress.
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Affiliation(s)
- Cassandra Uchida
- Angiogenesis Research Group, Faculty of Health, York University, 4700 Keele St., Toronto, ON M3J 1P3, Canada
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19
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Kim HI, Saldova R, Park JH, Lee YH, Harvey DJ, Wormald MR, Wynne K, Elia G, Kim HJ, Rudd PM, Lee ST. The presence of outer arm fucose residues on the N-glycans of tissue inhibitor of metalloproteinases-1 reduces its activity. J Proteome Res 2013; 12:3547-60. [PMID: 23815085 DOI: 10.1021/pr400276r] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Tissue inhibitor of metalloproteinases-1 (TIMP-1) inhibits matrix metalloproteinases (MMPs) by binding at a 1:1 stoichiometry. Here we have shown the involvement of N-glycosylation in the MMP inhibitory ability of TIMP-1. TIMP-1, purified from HEK 293 cells overexpressing TIMP-1 (293 TIMP-1), showed less binding and inhibitory abilities to MMPs than TIMP-1 purified from fibroblasts or SF9 insect cells infected with TIMP-1 baculovirus. Following deglycosylation of TIMP-1, all forms of TIMP-1 showed similar levels of MMP binding and inhibition, suggesting that glycosylation is involved in the regulation of these TIMP-1 activities. Analysis of the N-glycan structures showed that SF9 TIMP-1 has the simplest N-glycan structures, followed by fibroblast TIMP-1 and 293 TIMP-1, in order of increasing complexity in their N-glycan structures. Further analyses showed that cleavage of outer arm fucose residues from the N-glycans of 293 TIMP-1 or knockdown of both FUT4 and FUT7 (which encode for fucosyltransferases that add outer arm fucose residues to N-glycans) enhanced the MMP-binding and catalytic abilities of 293 TIMP-1, bringing them up to the levels of the other TIMP-1. These results demonstrate that the ability of TIMP-1 to inhibit MMPs is at least in part regulated by outer arm fucosylation of its N-glycans.
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Affiliation(s)
- Han Ie Kim
- Department of Biochemistry, College of Science and Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea
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Batra J, Robinson J, Soares AS, Fields AP, Radisky DC, Radisky ES. Matrix metalloproteinase-10 (MMP-10) interaction with tissue inhibitors of metalloproteinases TIMP-1 and TIMP-2: binding studies and crystal structure. J Biol Chem 2012; 287:15935-46. [PMID: 22427646 DOI: 10.1074/jbc.m112.341156] [Citation(s) in RCA: 91] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Matrix metalloproteinase 10 (MMP-10, stromelysin-2) is a secreted metalloproteinase with functions in skeletal development, wound healing, and vascular remodeling; its overexpression is also implicated in lung tumorigenesis and tumor progression. To understand the regulation of MMP-10 by tissue inhibitors of metalloproteinases (TIMPs), we have assessed equilibrium inhibition constants (K(i)) of putative physiological inhibitors TIMP-1 and TIMP-2 for the active catalytic domain of human MMP-10 (MMP-10cd) using multiple kinetic approaches. We find that TIMP-1 inhibits the MMP-10cd with a K(i) of 1.1 × 10(-9) M; this interaction is 10-fold weaker than the inhibition of the similar MMP-3 (stromelysin-1) catalytic domain (MMP-3cd) by TIMP-1. TIMP-2 inhibits the MMP-10cd with a K(i) of 5.8 × 10(-9) M, which is again 10-fold weaker than the inhibition of MMP-3cd by this inhibitor (K(i) = 5.5 × 10(-10) M). We solved the x-ray crystal structure of TIMP-1 bound to the MMP-10cd at 1.9 Å resolution; the structure was solved by molecular replacement and refined with an R-factor of 0.215 (R(free) = 0.266). Comparing our structure of MMP-10cd·TIMP-1 with the previously solved structure of MMP-3cd·TIMP-1 (Protein Data Bank entry 1UEA), we see substantial differences at the binding interface that provide insight into the differential binding of stromelysin family members to TIMP-1. This structural information may ultimately assist in the design of more selective TIMP-based inhibitors tailored for specificity toward individual members of the stromelysin family, with potential therapeutic applications.
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Affiliation(s)
- Jyotica Batra
- Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Jacksonville, Florida 32224, USA
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Abstract
Gelatin zymography is a simple yet powerful method to detect proteolytic enzymes capable of degrading gelatin from various biological sources. It is particularly useful for the assessment of two key members of the matrix metalloproteinase family, MMP-2 (gelatinase A) and MMP-9 (gelatinase B), due to their potent gelatin-degrading activity. This polyacrylamide gel electrophoresis-based method can provide a reliable assessment of the type of gelatinase, relative amount, and activation status (latent, compared with active enzyme forms) in cultured cells, tissues, and biological fluids. The method can be used to investigate factors that regulate gelatinase expression and modulate zymogen activation in experimental systems. The system provides information on the pattern of gelatinase expression and activation in human cancer tissues and how this relates to cancer progression. Interpretation of the data obtained in gelatin zymography requires a thorough understanding of the principles and pitfalls of the technique; this is particularly important when evaluating enzyme levels and the presence of active gelatinase species. If properly used, gelatin zymography is an excellent tool for the study of gelatinases in biological systems.
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Mazanowska O, Kamińska D, Krajewska M, Żabińska M, Kopeć W, Boratyńska M, Chudoba P, Patrzalek D, Klinger M. Imbalance of Metallaproteinase/Tissue Inhibitors of Metalloproteinase System in Renal Transplant Recipients With Chronic Allograft Injury. Transplant Proc 2011; 43:3000-3. [DOI: 10.1016/j.transproceed.2011.08.012] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/16/2022]
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Shiozawa S, Tsumiyama K, Yoshida K, Hashiramoto A. Pathogenesis of Joint Destruction in Rheumatoid Arthritis. Arch Immunol Ther Exp (Warsz) 2011; 59:89-95. [DOI: 10.1007/s00005-011-0116-3] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2010] [Accepted: 09/20/2010] [Indexed: 12/13/2022]
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Kagadis GC, Loudos G, Katsanos K, Langer SG, Nikiforidis GC. In vivosmall animal imaging: Current status and future prospects. Med Phys 2010; 37:6421-42. [DOI: 10.1118/1.3515456] [Citation(s) in RCA: 108] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
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Eisenach PA, Roghi C, Fogarasi M, Murphy G, English WR. MT1-MMP regulates VEGF-A expression through a complex with VEGFR-2 and Src. J Cell Sci 2010; 123:4182-93. [PMID: 21062896 DOI: 10.1242/jcs.062711] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Membrane-type-1 matrix metalloproteinase (MT1-MMP) is a zinc-dependent type-I transmembrane metalloproteinase involved in pericellular proteolysis, migration and invasion, with elevated levels correlating with a poor prognosis in cancer. MT1-MMP-mediated transcriptional regulation of genes in cancer cells can contribute to tumour growth, although this is poorly understood at a mechanistic level. In this study, we investigated the mechanism by which MT1-MMP regulates the expression of VEGF-A in breast cancer cells. We discovered that MT1-MMP regulates VEGFR-2 cell surface localisation and forms a complex with VEGFR-2 and Src that is dependent on the MT1-MMP hemopexin domain and independent of its catalytic activity. Although the localisation of VEGFR-2 was independent of the catalytic and intracellular domain of MT1-MMP, intracellular signalling dependent on VEGFR-2 activity leading to VEGF-A transcription still required the MT1-MMP catalytic and intracellular domain, including residues Y573, C574 and DKV582. However, there was redundancy in the function of the catalytic activity of MT1-MMP, as this could be substituted with MMP-2 or MMP-7 in cells expressing inactive MT1-MMP. The signalling cascade dependent on the MT1-MMP-VEGFR-2-Src complex activated Akt and mTOR, ultimately leading to increased VEGF-A transcription.
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Affiliation(s)
- Patricia A Eisenach
- University of Cambridge, Department of Oncology, Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK
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Van Steenkiste M, Oltenfreiter R, Frankenne F, Vervoort L, Maquoi E, Noel A, Foidart JM, Van De Wiele C, De Vos F. Membrane type 1 matrix metalloproteinase detection in tumors, using the iodinated endogenous [123I]-tissue inhibitor 2 of metalloproteinases as imaging agent. Cancer Biother Radiopharm 2010; 25:511-20. [PMID: 20854210 DOI: 10.1089/cbr.2010.0789] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Matrix metalloproteinases (MMPs) are principal participants in tumor development. In addition to serve as a useful biochemical marker, MMP expression may also provide a target for the diagnostic in vivo imaging of tumors, using a radiolabeled inhibitor. This study investigates the use of membrane type 1 (MT1)-MMP as target for in vivo tumor diagnosis. Specific binding of the endogenous tissue inhibitor of metalloproteinase-2 (TIMP-2) to MT1-MMP has been previously described. In this study, biodistribution and imaging experiments were performed on MT1-MMP-overexpressing (S.1.5) and control (C.IV.3) tumor-inoculated mice using [(123)I]-recombinant human TIMP-2 (rhTIMP-2) as radioligand and [(123)I]-rhTIMP-1 as control. The expression profile was controlled in vitro and on tumor extracts. rhTIMP-2 as well as rhTIMP-1 were labeled using the Iodogen method and characterized. Biodistribution of [(123)I]-rhTIMP-2 showed a tumor uptake of 2.87% ± 1.58% ID/g at 3 hours postinjection in S.1.5. Tumor values of [(123)I]-rhTIMP-1 and [(123)I]-rhTIMP-2 evaluated in S.1.5 and C.IV.3, respectively, were significantly lower. Planar imaging revealed significant uptake of [(123)I]-rhTIMP-2 in S.1.5 compared with contralateral background areas. This could not be observed in C.IV.3 and with [(123)I]-rhTIMP-1 in S.1.5. All tumors were well established (200-800 mg). These results suggest that rhTIMP-2 holds potential for development of radiotracers for in vivo imaging in overexpressing MT1-MMP but not in similar tumors that do not express this protease.
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Affiliation(s)
- Magali Van Steenkiste
- Laboratory of Radiopharmacy, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.
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Kinetic analysis of the inhibition of matrix metalloproteinases: lessons from the study of tissue inhibitors of metalloproteinases. Methods Mol Biol 2010. [PMID: 20135297 DOI: 10.1007/978-1-60327-299-5_25] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register]
Abstract
Tissue inhibitors of metalloproteinases (TIMPs) are a group of highly potent inhibitors of matrix metalloproteinases (MMPs) and disintegrin metalloproteinases (ADAMs). The high affinity and "tight-binding" nature of the inhibition of MMPs or ADAMs by TIMPs presents challenges for the determination of both equilibrium and dissociation rate constants of these inhibitory events. Methodologies that enable some of these challenges to be overcome are described in this chapter and represent valuable lessons for the in vitro assessment of MMP or ADAM inhibitors within a drug discovery context.
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Stechmiller J, Cowan L, Schultz G. The Role of Doxycycline as a Matrix Metalloproteinase Inhibitor for the Treatment of Chronic Wounds. Biol Res Nurs 2009; 11:336-44. [DOI: 10.1177/1099800409346333] [Citation(s) in RCA: 66] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Many chronic wounds fail to heal with conventional therapy, resulting in disability and impaired quality of life. New technologies using recombinant growth factors, autologous growth factors, or bioengineered skin—tissue substitutes have been shown to be effective, but these treatments are costly. An effective, low-cost treatment to improve healing of chronic wounds is needed. The molecular environment of chronic wounds, like many other chronic inflammatory diseases, contains abnormally high levels of proinflammatory cytokines (tumor necrosis factor [TNF]-α and interleukin [IL]-1β]) and matrix metalloproteinases (MMPs), which impair normal wound healing. In animal models and clinical studies of ulcerative diseases, doxycycline, an inexpensive and Food and Drug Administration (FDA)-approved antibiotic, appears to inhibit members of the MMP superfamily like MMPs and TNF-α-converting enzyme (TACE). This article provides an overview of the roles of MMPs and intrinsic tissue inhibitors of metalloproteinases (TIMPs) in wound healing and the damaging effects of chronically elevated levels of MMPSs in chronic wounds. It also explores the use of topical doxycycline, a synthetic MMP inhibitor (MMPI), to enhance healing of chronic wounds.
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Affiliation(s)
| | - Linda Cowan
- North Florida/South Georgia Veterans Health Systems,
University of Florida, Gainesville, Florida
| | - Gregory Schultz
- Department of Obstetrics and Gynecology, University
of Florida, Gainesville, Florida
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Ji RR, Xu ZZ, Wang X, Lo EH. Matrix metalloprotease regulation of neuropathic pain. Trends Pharmacol Sci 2009; 30:336-40. [PMID: 19523695 PMCID: PMC2706286 DOI: 10.1016/j.tips.2009.04.002] [Citation(s) in RCA: 136] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2009] [Revised: 04/10/2009] [Accepted: 04/14/2009] [Indexed: 12/13/2022]
Abstract
Neuropathic pain affects millions of people globally and could be a disease on its own right. Current treatments focus on blocking neurotransmission and have resulted in limited success. Recent progress points to an important role of neuroinflammation in the pathogenesis of neuropathic pain. Matrix metalloproteases (MMPs) comprise a large family of zinc endopeptidases that have been implicated in the generation of neuroinflammation via cleavage of extracellular matrix proteins and activation of proinflammatory cytokines and chemokines. However, little is known about the role of MMPs in chronic pain regulation. Our recent study has shown that neuropathic pain development in the early and late phase requires MMP-9 and MMP-2, respectively. Inhibition of MMP-9 or MMP-2 might provide a new strategy for the prevention and treatment of neuropathic pain.
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Affiliation(s)
- Ru-Rong Ji
- Pain Research Center, Department of Anesthesiology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
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Sela-Passwell N, Rosenblum G, Shoham T, Sagi I. Structural and functional bases for allosteric control of MMP activities: can it pave the path for selective inhibition? BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2009; 1803:29-38. [PMID: 19406173 DOI: 10.1016/j.bbamcr.2009.04.010] [Citation(s) in RCA: 109] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/19/2009] [Revised: 04/20/2009] [Accepted: 04/21/2009] [Indexed: 01/01/2023]
Abstract
The zinc-dependent matrix metalloproteinases (MMPs) belong to a large family of structurally homologous enzymes. These enzymes are involved in a wide variety of biological processes ranging from physiological cell proliferation and differentiation to pathological states associated with tumor metastasis, inflammation, tissue degeneration, and cell death. Controlling the enzymatic activity of specific individual MMPs by antagonist molecules is highly desirable, first, for studying their individual roles, and second as potential therapeutic agents. However, blocking the enzymatic activity with synthetic small inhibitors appears to be an extremely difficult task. Thus, this is an unmet need presumably due to the high structural homology between MMP catalytic domains. Recent reports have recognized a potential role for exosite or allosteric protein regions, distinct from the extended catalytic pocket, in mediating MMP activation and substrate hydrolysis. This raises the possibility that MMP enzymatic and non-enzymatic activities may be modified via antagonist molecules targeted to such allosteric sites or to alternative enzyme domains. In this review, we discuss the structural and functional bases for potential allosteric control of MMPs and highlight potential alternative enzyme domains as targets for designing highly selective MMP inhibitors.
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31
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Walker 256 cancer cells secrete tissue inhibitor of metalloproteinase-free metalloproteinase-9. Mol Cell Biochem 2009; 328:189-99. [DOI: 10.1007/s11010-009-0089-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2008] [Accepted: 03/11/2009] [Indexed: 10/21/2022]
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Tveita A, Rekvig OP, Zykova SN. Glomerular matrix metalloproteinases and their regulators in the pathogenesis of lupus nephritis. Arthritis Res Ther 2008; 10:229. [PMID: 19090960 PMCID: PMC2656222 DOI: 10.1186/ar2532] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Lupus nephritis is a major contributor to morbidity and mortality in systemic lupus erythematosus, but little is known about the pathogenic processes that underlie the progressive decay in renal function. A common finding in lupus nephritis is thickening of glomerular basement membranes associated with immune complex deposition. It has been speculated that alterations in the synthesis or degradation of membrane components might contribute to such changes, and thereby to initiation and progression of nephritis through facilitation of immune complex deposition. Matrix metalloproteinases (MMPs) are enzymes that are intimately involved in the turnover of major glomerular basement membrane constituents, including collagen IV and laminins. Alterations in the expression and activity of MMPs have been described in a number of renal diseases, suggesting their relevance to the pathogenesis of various glomerulopathies. The same is true for their natural inhibitors, the tissue inhibitor of metalloproteinase family. Recent data from our group have identified an increase in proteolytic activity within the glomerulus coinciding with the development of proteinuria in the mouse model of systemic lupus erythematosus. (NXB x NZW)F1 Here we review current understanding of MMP/tissue inhibitor of metalloproteinase function within the kidney, and discuss their possible involvement in the development and progression of lupus nephritis.
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Affiliation(s)
- Anders Tveita
- Department of Biochemistry, Medical Faculty, Institute of Medical Biology, University of Tromsø, Tromsø, Norway.
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33
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Lockwood CJ, Oner C, Uz YH, Kayisli UA, Huang SJ, Buchwalder LF, Murk W, Funai EF, Schatz F. Matrix metalloproteinase 9 (MMP9) expression in preeclamptic decidua and MMP9 induction by tumor necrosis factor alpha and interleukin 1 beta in human first trimester decidual cells. Biol Reprod 2008; 78:1064-72. [PMID: 18276934 PMCID: PMC3045968 DOI: 10.1095/biolreprod.107.063743] [Citation(s) in RCA: 92] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022] Open
Abstract
Extravillous trophoblasts (EVTs) invade human decidua via sequential integrin-mediated binding and proteolysis of basement membrane proteins in the extracellular matrix (ECM). In preeclampsia, shallow EVT invasion impairs spiral artery and arteriole remodeling to reduce uteroplacental blood flow. Excess decidual cell-expressed matrix metalloproteinases (MMPs) 2 and 9, in response to preeclampsia-related interleukin 1 beta (IL1B) and tumor necrosis factor alpha (TNF), may inappropriately degrade these basement membrane proteins and impede EVT invasion. This study found significantly higher immunohistochemical MMP9 levels in decidual cells and adjacent interstitial trophoblasts in placental sections of preeclamptic versus gestational age-matched control women. In contrast, immunostaining for MMP2 and tissue inhibitor of matrix metalloproteinases 1 and 2 (TIMP1 and TIMP2) were similar in preeclamptic and control groups. First-trimester decidual cells were incubated with estradiol (E(2)) or E(2) + medroxyprogesterone acetate (MPA), with or without TNF or IL1B. As measured by ELISA, both cytokines elicited concentration-dependent increases in secreted MMP9 levels that were unaffected by MPA. In contrast, secreted levels of MMP2, TIMP1, and TIMP2 were unchanged in all treatment groups. Substrate gel zymography and Western blotting confirmed that each cytokine increased secreted levels of MMP9 but not MMP2. Similarly, quantitative RT-PCR found that TNF and IL1B enhanced MMP9, but not MMP2, mRNA levels. At the implantation site, inflammatory cytokine-enhanced MMP9 may promote preeclampsia by disrupting the decidual ECM to interfere with normal stepwise EVT invasion.
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Affiliation(s)
- Charles J. Lockwood
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut 06510
| | - Ceyda Oner
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut 06510
| | - Yesim H. Uz
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut 06510
- Department of Histology and Embryology, Trakya University Medical Faculty, 22030 Edirne, Turkey
| | - Umit A. Kayisli
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut 06510
| | - S. Joseph Huang
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut 06510
| | - Lynn F. Buchwalder
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut 06510
| | - William Murk
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut 06510
| | - Edmund F. Funai
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut 06510
| | - Frederick Schatz
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut 06510
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Krubasik D, Eisenach PA, Kunz-Schughart LA, Murphy G, English WR. Granulocyte-macrophage colony stimulating factor induces endothelial capillary formation through induction of membrane-type 1 matrix metalloproteinase expression in vitro. Int J Cancer 2008; 122:1261-72. [PMID: 18027871 DOI: 10.1002/ijc.23234] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
In our study, we examined the mechanism by which granulocyte-macrophage colony stimulating factor (GM-CSF) regulates angiogenesis using in vitro models. GM-CSF significantly increased precapillary sprout-like formation from endothelial cell spheroids seeded in type-I collagen gels and tubule formation on coculture of endothelial cells with fibroblasts. In both cases, sprout and tubule formation was highly dependent on metalloproteinase activity. Tissue Inhibitor of metalloproteinase (TIMP) profiling in the spheroid and coculture models showed inhibition by TIMP-2 but not by TIMP-1, indicative of activity of membrane-type matrix metalloproteinases (MT-MMPs). GM-CSF induced sprout formation in spheroids was found to be potently inhibited by siRNA specific for MT1-MMP. Subsequent analysis showed that GM-CSF transiently increased MT1-MMP mRNA in endothelial cells in a MEK-dependent mechanism, which led to increased surface levels of MT1-MMP. This was accompanied by an increase in MT1-MMP-dependent degradation of DQ-collagen by lysates of GM-CSF stimulated endothelial cells. GM-CSF did not increase MT1-MMP levels in fibroblasts. The effect of GM-CSF on endothelial cell sprout formation could be mimicked by adenoviral transduction of intact spheroids with virus expressing MT1-MMP, but not by transduction of endothelial cells before spheroid formation, suggesting that upregulation of MT1-MMP must only occur in cells directly involved in tubule formation.
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Affiliation(s)
- Davia Krubasik
- Cancer Research UK, Cambridge Research Institute, Cambridge, United Kingdom
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35
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Kawasaki Y, Xu ZZ, Wang X, Park JY, Zhuang ZY, Tan PH, Gao YJ, Roy K, Corfas G, Lo EH, Ji RR. Distinct roles of matrix metalloproteases in the early- and late-phase development of neuropathic pain. Nat Med 2008; 14:331-6. [PMID: 18264108 PMCID: PMC2279180 DOI: 10.1038/nm1723] [Citation(s) in RCA: 601] [Impact Index Per Article: 35.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2007] [Accepted: 01/04/2008] [Indexed: 12/11/2022]
Abstract
Treatment of neuropathic pain, triggered by multiple insults to the nervous system, is a clinical challenge because the underlying mechanisms of neuropathic pain development remain poorly understood. Most treatments do not differentiate between different phases of neuropathic pain pathophysiology and simply focus on blocking neurotransmission, producing transient pain relief. Here, we report that early- and late-phase neuropathic pain development in rats and mice after nerve injury require different matrix metalloproteinases (MMPs). After spinal nerve ligation, MMP-9 shows a rapid and transient upregulation in injured dorsal root ganglion (DRG) primary sensory neurons consistent with an early phase of neuropathic pain, whereas MMP-2 shows a delayed response in DRG satellite cells and spinal astrocytes consistent with a late phase of neuropathic pain. Local inhibition of MMP-9 by an intrathecal route inhibits the early phase of neuropathic pain, whereas inhibition of MMP-2 suppresses the late phase of neuropathic pain. Further, intrathecal administration of MMP-9 or MMP-2 is sufficient to produce neuropathic pain symptoms. After nerve injury, MMP-9 induces neuropathic pain through interleukin-1beta cleavage and microglial activation at early times, whereas MMP-2 maintains neuropathic pain through interleukin-1beta cleavage and astrocyte activation at later times. Inhibition of MMP may provide a novel therapeutic approach for the treatment of neuropathic pain at different phases.
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Affiliation(s)
- Yasuhiko Kawasaki
- Pain Research Center, Department of Anesthesiology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115
| | - Zhen-Zhong Xu
- Pain Research Center, Department of Anesthesiology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115
| | - Xiaoying Wang
- Neuroprotection Research Laboratory, Departments of Neurology and Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129
| | - Jong-Yeon Park
- Pain Research Center, Department of Anesthesiology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115
| | - Zhi-Ye Zhuang
- Pain Research Center, Department of Anesthesiology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115
| | - Ping-Heng Tan
- Pain Research Center, Department of Anesthesiology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115
| | - Yong-Jing Gao
- Pain Research Center, Department of Anesthesiology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115
| | - Kristine Roy
- Devision of Neuroscience, Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115
| | - Gabriel Corfas
- Devision of Neuroscience, Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115
| | - Eng H. Lo
- Neuroprotection Research Laboratory, Departments of Neurology and Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129
| | - Ru-Rong Ji
- Pain Research Center, Department of Anesthesiology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115
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Garvican ER, Vaughan-Thomas A, Redmond C, Clegg PD. MT3-MMP (MMP-16) is downregulated by in vitro cytokine stimulation of cartilage, but unaltered in naturally occurring equine osteoarthritis and osteochondrosis. Connect Tissue Res 2008; 49:62-7. [PMID: 18382891 DOI: 10.1080/03008200801913338] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Matrix degradation by metalloproteinases is considered a key feature in the loss of articular cartilage seen in many joint diseases. Membrane-type matrix metalloproteinase-3 (MT3-MMP) expression is elevated in human cartilage in end-stage osteoarthritis. We investigated whether MT3-MMP is similarly regulated in cartilage in two naturally occurring arthropathies in vivo and whether proinflammatory cytokines regulate its expression in vitro. MT3-MMP expression was evaluated in cartilage from horses with osteoarthritis and osteochondrosis and compared with age- and site-matched normal cartilage. MT3-MMP also was measured in normal cartilage stimulated with proinflammatory cytokines. MT3-MMP expression was not significantly altered in either osteoarthritis or osteochondrosis cartilage. However, gene expression was significantly downregulated by the addition of recombinant human interleukin-1beta, oncostatin M, or tumor necrosis factor-alpha to normal cartilage explants. The results suggest that MT3-MMP may not have a role in matrix destruction in equine cartilage diseases. Further work is required to characterize its regulation and function.
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Affiliation(s)
- E R Garvican
- Musculoskeletal Research Group, University of Liverpool, Wirral, United Kingdom.
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Shuo T, Aono S, Nakanishi K, Tokita Y, Kuroda Y, Ida M, Matsui F, Maruyama H, Kaji T, Oohira A. Ectodomain shedding of neuroglycan C, a brain-specific chondroitin sulfate proteoglycan, by TIMP-2- and TIMP-3-sensitive proteolysis. J Neurochem 2007; 102:1561-1568. [PMID: 17532789 DOI: 10.1111/j.1471-4159.2007.04658.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Neuroglycan C (NGC) is a transmembrane-type of chondroitin sulfate proteoglycan with an epidermal growth factor (EGF)-like module that is exclusively expressed in the CNS. Because ectodomain shedding is a common processing step for many transmembrane proteins, we examined whether NGC was subjected to proteolytic cleavage. Western blotting demonstrated the occurrence of a soluble form of NGC with a 75 kDa core glycoprotein in the soluble fraction of the young rat cerebrum. In contrast, full-length NGC with a 120 kDa core glycoprotein and its cytoplasmic fragment with a molecular size of 35 kDa could be detected in the membrane fraction. The soluble form of NGC was also detectable in culture media of fetal rat neurons, and the full-length form existed in cell layers. The amount of the soluble form in culture media was decreased by adding a physiological protease inhibitor such as a tissue inhibitor of metalloproteinase (TIMP)-2 or TIMP-3, but not by adding TIMP-1. Both EGF-like and neurite outgrowth-promoting activity of the NGC ectodomain may be regulated by this proteolytic processing.
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Affiliation(s)
- Takuya Shuo
- Department of Perinatology and Neuroglycoscience, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Aichi, JapanDepartment of Neurochemistry, Nagoya University Graduate School of Medicine, Nagoya, JapanDepartment of Environmental Health, Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Japan
| | - Sachiko Aono
- Department of Perinatology and Neuroglycoscience, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Aichi, JapanDepartment of Neurochemistry, Nagoya University Graduate School of Medicine, Nagoya, JapanDepartment of Environmental Health, Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Japan
| | - Keiko Nakanishi
- Department of Perinatology and Neuroglycoscience, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Aichi, JapanDepartment of Neurochemistry, Nagoya University Graduate School of Medicine, Nagoya, JapanDepartment of Environmental Health, Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Japan
| | - Yoshihito Tokita
- Department of Perinatology and Neuroglycoscience, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Aichi, JapanDepartment of Neurochemistry, Nagoya University Graduate School of Medicine, Nagoya, JapanDepartment of Environmental Health, Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Japan
| | - Yoshiyuki Kuroda
- Department of Perinatology and Neuroglycoscience, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Aichi, JapanDepartment of Neurochemistry, Nagoya University Graduate School of Medicine, Nagoya, JapanDepartment of Environmental Health, Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Japan
| | - Michiru Ida
- Department of Perinatology and Neuroglycoscience, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Aichi, JapanDepartment of Neurochemistry, Nagoya University Graduate School of Medicine, Nagoya, JapanDepartment of Environmental Health, Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Japan
| | - Fumiko Matsui
- Department of Perinatology and Neuroglycoscience, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Aichi, JapanDepartment of Neurochemistry, Nagoya University Graduate School of Medicine, Nagoya, JapanDepartment of Environmental Health, Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Japan
| | - Hiroyo Maruyama
- Department of Perinatology and Neuroglycoscience, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Aichi, JapanDepartment of Neurochemistry, Nagoya University Graduate School of Medicine, Nagoya, JapanDepartment of Environmental Health, Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Japan
| | - Toshiyuki Kaji
- Department of Perinatology and Neuroglycoscience, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Aichi, JapanDepartment of Neurochemistry, Nagoya University Graduate School of Medicine, Nagoya, JapanDepartment of Environmental Health, Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Japan
| | - Atsuhiko Oohira
- Department of Perinatology and Neuroglycoscience, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Aichi, JapanDepartment of Neurochemistry, Nagoya University Graduate School of Medicine, Nagoya, JapanDepartment of Environmental Health, Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Japan
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Vidal A, Sabatini M, Rolland-Valognes G, Renard P, Madelmont JC, Mounetou E. Synthesis and in vitro evaluation of targeted tetracycline derivatives: Effects on inhibition of matrix metalloproteinases. Bioorg Med Chem 2007; 15:2368-74. [PMID: 17267227 DOI: 10.1016/j.bmc.2007.01.026] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2006] [Revised: 12/22/2006] [Accepted: 01/17/2007] [Indexed: 11/19/2022]
Abstract
Among other non-antibiotic properties, tetracyclines inhibit matrix metalloproteinases and are currently under study for the treatment of osteoarthritis. Quaternary ammonium conjugates of tetracyclines were synthesized by direct alkylation of the amine function at the 4-position with methyl iodide. When tested in vitro, they inhibited cytokine-induced MMP expression to a lesser extent than parent tetracyclines. This was compensated by an improved inhibition of MMP catalytic activity. Since inhibition of collagen degradation was maintained these derivatives could be potent drug candidates for cartilage-targeted chondroprotective treatment.
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Aoki T, Kataoka H, Morimoto M, Nozaki K, Hashimoto N. Macrophage-derived matrix metalloproteinase-2 and -9 promote the progression of cerebral aneurysms in rats. Stroke 2006; 38:162-9. [PMID: 17122420 DOI: 10.1161/01.str.0000252129.18605.c8] [Citation(s) in RCA: 235] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND AND PURPOSE Mechanisms of initiation, progression and rupture of cerebral aneurysms have not yet been fully understood despite its clinical significance. Matrix metalloproteinases (MMPs) are a family of proteinases which are involved in the remodeling of vascular walls. In the present study, we investigated the significance of MMPs in the progression of cerebral aneurysms. METHODS Cerebral aneurysms were experimentally induced in 7-week-old male Sprague-Dawley rats. MMP-2 and MMP-9 expression was examined by immunohistochemistry and RT-PCR. Gelatinase activity in aneurysmal walls was assessed by in situ zymography. A selective inhibitor for MMP-2, -9 and -12, tolylsam, was used to examine the effect of inhibition of MMP-2 and MMP-9. RESULTS Macrophages infiltrated in arterial walls of experimentally induced rat cerebral aneurysms and expressed MMP-2 and -9. Macrophage infiltration and MMP expression was increased with the progression of aneurysms. Gelatinase activity attributable to MMP-2 and MMP-9 increased in arterial walls of rat cerebral aneurysms. Furthermore, tolylsam reduced the ratio of advanced aneurysms in our rat model. CONCLUSIONS These data suggest that macrophage-derived MMP-2 and -9 may play an important role in the progression of cerebral aneurysms. The findings of this study will shed a new light into the pathogenesis of cerebral aneurysms and highlight the importance of inflammatory response causing the degeneration of extracellular matrix in the process of this disease.
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Affiliation(s)
- Tomohiro Aoki
- Kyoto University, Graduate School of Medicine, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, Japan
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40
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Yates PJ, Nicholson ML. The aetiology and pathogenesis of chronic allograft nephropathy. Transpl Immunol 2006; 16:148-57. [PMID: 17138047 DOI: 10.1016/j.trim.2006.10.001] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2006] [Revised: 10/03/2006] [Accepted: 10/06/2006] [Indexed: 11/20/2022]
Abstract
Renal transplantation is the ultimate form of renal replacement therapy, and is the treatment of choice for many patients with end-stage renal failure. The advent of calcineurin inhibitor based immunosuppression resulted in the 1-year renal allograft failure rate dropping from around 50% twenty years ago to less than 10% in more recent times. Despite a massive improvement in renal allograft survival in the first year following transplantation 10-year graft survival can be as low as 50%. Chronic allograft nephropathy (CAN) is recognised as the main cause of renal allograft failure following the first year after transplantation. The diagnosis of CAN can only be made histologically. Typically biopsy specimens in grafts with CAN demonstrate an overall fibrotic appearance effecting the vascular endothelium, renal tubules, interstitium, and glomerulus. The risk factors for CAN are divided into alloimmune and alloimmune independent. Alloimmune dependent factors include acute cellular rejection, severity of rejection, subclinical rejection and HLA mismatch. Alloimmune independent factors such as delayed graft function, donor age, Cytomegalovirus infection, donor/recipient co-morbidity and of course calcineurin inhibitor toxicity are important in the development of CAN. The pathogenesis of CAN is complex, multifactorial, and unfortunately incompletely understood. There are a number of pivotal steps in the initiation and propagation of the fibrosis seen in biopsy specimens from kidneys with CAN. Endothelial activation in response to one or more of the aforementioned risk factors stimulates leukocyte activation and recruitment. Recruited leukocytes subsequently infiltrate through the endothelium and induce key effector cells to secrete excessive and abnormal extracellular matrix (ECM). Enhanced deposition of ECM is a histological hallmark of CAN. This paper aims to present a concise yet accurate and up-to-date review of the literature concerning the aetiological factors and pathological processes which are present in the generation of CAN.
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Affiliation(s)
- P J Yates
- Division of Transplant Surgery, Department of Cardiovascular Sciences, University of Leicester, Leicester, LE5 4PW UK.
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Josyula AB, Poplin GS, Kurzius-Spencer M, McClellen HE, Kopplin MJ, Stürup S, Clark Lantz R, Burgess JL. Environmental arsenic exposure and sputum metalloproteinase concentrations. ENVIRONMENTAL RESEARCH 2006; 102:283-90. [PMID: 16487958 DOI: 10.1016/j.envres.2006.01.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/27/2005] [Revised: 12/07/2005] [Accepted: 01/09/2006] [Indexed: 05/06/2023]
Abstract
Exposure to arsenic in drinking water is associated with an increased rate of lung cancer. The objective of this study was to determine whether arsenic exposure at relatively low concentrations (approximately 20 microg/L) is associated with changes in biomarkers of lung inflammation, as measured by the ratio of sputum metalloproteinase and antiproteinase activity. A total of 73 subjects residing in Ajo and Tucson, Arizona were recruited for this cross-sectional study. Tap water and first morning void urine were analyzed for arsenic. Matrix metalloproteinase 2 (MMP-2), 9 (MMP-9) and tissue inhibitor of metalloproteinase 1 (TIMP-1) were measured in induced sputum. Household tap water arsenic levels in Ajo (20.3+/-3.7 microg/L) were higher than in those Tucson (4.0+/-2.3 microg/L), as were mean urinary total inorganic arsenic levels (29.1+/-20.4 and 11.0+/-12.0 microg/L, respectively). Log-normalized MMP-2, MMP-9, and TIMP-1 concentrations in sputum were not significantly different between towns. However, after adjusting for town, asthma, diabetes, urinary monomethylarsonic acid/inorganic arsenic, and smoking history, total urinary arsenic was negatively associated with MMP-2 and TIMP-1 levels in sputum and positively associated with the ratio of MMP-2/TIMP-1 and MMP-9/TIMP-1 in sputum. Increased sputum proteinase/antiproteinase activity suggests a potential toxic mechanism for low-level arsenic exposure.
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Iyer S, Wei S, Brew K, Acharya KR. Crystal structure of the catalytic domain of matrix metalloproteinase-1 in complex with the inhibitory domain of tissue inhibitor of metalloproteinase-1. J Biol Chem 2006; 282:364-71. [PMID: 17050530 DOI: 10.1074/jbc.m607625200] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The mammalian collagenases are a subgroup of the matrix metalloproteinases (MMPs) that are uniquely able to cleave triple helical fibrillar collagens. Collagen breakdown is an essential part of extracellular matrix turnover in key physiological processes including morphogenesis and wound healing; however, unregulated collagenolysis is linked to important diseases such as arthritis and cancer. The tissue inhibitors of metalloproteinases (TIMPs) function in controlling the activity of MMPs, including collagenases. We report here the structure of a complex of the catalytic domain of fibroblast collagenase (MMP-1) with the N-terminal inhibitory domain of human TIMP-1 (N-TIMP-1) at 2.54 A resolution. Comparison with the previously reported structure of the TIMP-1/stromelysin-1 (MMP-3) complex shows that the mechanisms of inhibition of both MMPs are generally similar, yet there are significant differences in the protein-protein interfaces in the two complexes. Specifically, the loop between beta-strands A and B of TIMP-1 makes contact with MMP-3 but not with MMP-1, and there are marked differences in the roles of individual residues in the C-D connector of TIMP-1 in binding to the two MMPs. Structural rearrangements in the bound MMPs are also strikingly different. This is the first crystallographic structure that contains the truncated N-terminal domain of a TIMP, which shows only minor differences from the corresponding region of the full-length protein. Differences in the interactions in the two TIMP-1 complexes provide a structural explanation for the results of previous mutational studies and a basis for designing new N-TIMP-1 variants with restricted specificity.
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Affiliation(s)
- Shalini Iyer
- Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK
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Van den Steen PE, Van Aelst I, Starckx S, Maskos K, Opdenakker G, Pagenstecher A. Matrix metalloproteinases, tissue inhibitors of MMPs and TACE in experimental cerebral malaria. J Transl Med 2006; 86:873-88. [PMID: 16865090 DOI: 10.1038/labinvest.3700454] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
Cerebral malaria (CM) is a life-threatening disorder and a major medical problem in developing countries. It is caused by the sequestration of malaria-infected erythrocytes onto brain endothelia, followed by blood-brain barrier (BBB) damage and neurological deficit. In the present study, matrix metalloproteinases (MMPs) were analysed in a mouse model of CM with Plasmodium berghei ANKA. Increased numbers of gelatinase B (MMP-9)-positive cells, which were also CD11b(+), were detected in the brain. In addition, activation of gelatinase B occurred in CM brains, and not in brains of mice with non-CM. However, selective genetic knockout of gelatinase B did not alter the clinical evolution of experimental CM. To study other protease balances, the mRNA expression levels of nine matrix metalloproteinases (MMPs), five membrane-type MMPs, TNF-alpha converting enzyme (TACE) and the four tissue inhibitors of metalloproteinases (TIMPs) were analysed during CM in different organs. Significant alterations in expression were observed, including increases of the mRNAs of MMP-3, -8, -13 and -14 in the spleen, MMP-8, -12, -13 and -14 in the liver and MMP-8 and -13 in the brain. Net gelatinolytic activity, independent of gelatinase B and inhibitable with EDTA, was detected in situ in the endothelia of blood vessels in CM brains, but not in brains of mice with non-CM, suggesting that metalloproteases, different from gelatinase B, are active in the BBB environment in CM. The increase in MMP expression in the brain was significantly less pronounced after infection of C57Bl/6 mice with the noncerebral strain P. berghei NK65, but it was similar in CM-susceptible C57Bl/6 and CM-resistant Balb/C mice upon infection with P. berghei ANKA. Furthermore, in comparison with C57Bl/6 mice, a larger increase in TIMP-1 and a marked, >30-fold induction in MMP-3 were found in the brains of Balb/C mice, suggesting possible protective roles for TIMP-1 and MMP-3.
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Abstract
Tissue inhibitors of metalloproteinases (TIMPs) are endogenous inhibitors of matrix metalloproteinases (MMPs) and the balance between MMPs/TIMPs regulates the extracellular matrix (ECM) turnover and remodeling during normal development and pathogenesis. Increasing evidence indicates a much more complex role for TIMPs during tumor progression and angiogenesis, in addition to their regulation of MMP-mediated ECM degradation. In this article, we review both the MMP-dependent and -independent actions of TIMPs for the regulation of cell death, cell proliferation, and angiogenesis, with a particular emphasis on TIMP-1 in the regulation of tetraspanin/integrin-mediated cell survival signal transduction pathways.
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Affiliation(s)
- Rosemarie Chirco
- Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, 540 East Canfield Avenue, Detroit, Michigan 48201, USA.
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Rhee JW, Lee KW, Sohn WJ, Lee Y, Jeon OH, Kwon HJ, Kim DS. Regulation of matrix metalloproteinase-9 gene expression and cell migration by NF-kappa B in response to CpG-oligodeoxynucleotides in RAW 264.7 cells. Mol Immunol 2006; 44:1393-400. [PMID: 16780951 DOI: 10.1016/j.molimm.2006.05.003] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2006] [Revised: 05/01/2006] [Accepted: 05/02/2006] [Indexed: 12/30/2022]
Abstract
Matrix metalloproteinase-9 (MMP-9) is a secreted type IV collagenase that plays an important role in the remodeling of the extracellular matrix (ECM) and the migration of normal and tumor cells. We have shown that CpG-ODN-induced migration of RAW 264.7 cell is regulated by MMP-9 activity by using tissue inhibitors of MMP-1 (TIMP-1). The MMP-9 gene expression was transcriptionally induced by CpG-ODN in a time-dependent manner. An MMP-9 promoter-reporter was activated by the stimulation of CpG-ODN and ectopical expression of NF-kappaB transcription factor. Inhibition of NF-kappaB nuclear localization by co-expression of a mutant IkappaBalpha protein blocked the CpG-ODN-induced MMP-9 promoter activation. BMS-345541, an IKK-2 inhibitor also inhibited the expression of MMP-9 gene induced by CpG-ODN. Direct binding of NF-kappaB protein to the promoter region of the MMP-9 was confirmed by chromatin immunoprecipitation using NF-kappaB antibody. These results lead us to a conclusion that NF-kappaB activation is required for MMP-9 gene expression. In summary, our data suggest that NF-kappaB-dependent expression of MMP-9 in response to CpG-ODN plays an important role in the recruitment of immune cells.
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Affiliation(s)
- Jae Won Rhee
- Department of Biochemistry and Institute of Life Science and Biotechnology, College of Science, Yonsei University, Seoul 120-749, Republic of Korea
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Stevenson TJ, Vinarsky V, Atkinson DL, Keating MT, Odelberg SJ. Tissue inhibitor of metalloproteinase 1 regulates matrix metalloproteinase activity during newt limb regeneration. Dev Dyn 2006; 235:606-16. [PMID: 16372340 DOI: 10.1002/dvdy.20654] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
Matrix metalloproteinase (MMP) activity is important for newt limb regeneration. In most biological processes that require MMP function, MMP activity is tightly controlled by a variety of mechanisms, including the coexpression of natural inhibitors. Here, we show that gene expression of one such inhibitor, tissue inhibitor of metalloproteinase 1 (NvTIMP1), is upregulated during the wound healing and dedifferentiation stages of regeneration when several MMPs are at their maximal expression levels. Newt MMPs and NvTIMP1 also exhibit similar spatial expression patterns during the early stages of limb regeneration. NvTIMP1 inhibits the proteolytic activity of regeneration-related newt MMPs and, like human TIMP1, can induce a weak mitogenic response in certain cell types. These results suggest that NvTIMP1 may be functioning primarily to maintain optimal levels of MMP activity during the early stages of limb regeneration, while possibly serving a secondary role as a mitogen.
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Affiliation(s)
- Tamara J Stevenson
- Department of Internal Medicine, Division of Cardiology, University of Utah Health Sciences Center, Salt Lake City, Utah 84132, USA
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Lee ER, Lamplugh L, Kluczyk B, Mort JS, Leblond CP. Protease analysis by neoepitope approach reveals the activation of MMP-9 is achieved proteolytically in a test tissue cartilage model involved in bone formation. J Histochem Cytochem 2006; 54:965-80. [PMID: 16709729 DOI: 10.1369/jhc.5a6789.2006] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
A principle of regulation of matrix metalloproteinase (MMP) activity has been introduced as the cysteine-switch mechanism of activation (Springman et al. 1990). According to this mechanism, a critical Cys residue found in the auto-inhibitory propeptide domain of latent proenzyme is important to determine whether or not activation is turned on or off. The mechanism further allows for multiple modes of activation. To determine whether or not activation is accomplished proteolytically within a rat test cartilage model, protease analysis by the neoepitope approach, which relies upon a set of antibodies, was applied. One is used to identify the MMP-9 proenzyme bearing the critical cysteine residue, the other to identify any enzyme present bearing a new NH2-terminus 89FQTFD. This is indicative of MMP-9 lacking the cysteine switch. The antibody set has been applied to frozen tissue sections and analyzed by light and electron microscopic methods. Results reveal that activation of the MMP-9 protease involves limited proteolysis resulting in propeptide domain release. Here we report the observed changes of protease form to indigenous cells and extracellular matrix, thereby making it possible to uncover the features of MMP-9 activation within a specified set of tissue circumstances where a cartilage model is transformed into definitive bone. This manuscript contains online supplemental material at http://www.jhc.org. Please visit this article online to view these materials.
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Affiliation(s)
- Eunice R Lee
- Electron Microscopy Unit, Joint Diseases Laboratory, Shriners Hospital for Children, and Division of Surgical Research, Department of Surgery, McGill University, Montreal, Quebec, H3G 1A6, Canada.
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Tsakadze NL, Sithu SD, Sen U, English WR, Murphy G, D'Souza SE. Tumor necrosis factor-alpha-converting enzyme (TACE/ADAM-17) mediates the ectodomain cleavage of intercellular adhesion molecule-1 (ICAM-1). J Biol Chem 2005; 281:3157-64. [PMID: 16332693 DOI: 10.1074/jbc.m510797200] [Citation(s) in RCA: 138] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Ectodomain shedding has emerged as an important regulatory step in the function of transmembrane proteins. Intercellular adhesion molecule-1 (ICAM-1), an adhesion receptor that mediates inflammatory and immune responses, undergoes shedding in the presence of inflammatory mediators and phorbol 12-myristate 13-acetate (PMA). The shedding of ICAM-1 in ICAM-1-transfected 293 cells upon PMA stimulation and in endothelial cells upon tumor necrosis factor-alpha stimulation was blocked by metalloproteinase inhibitors, whereas serine protease inhibitors were ineffective. p-Aminophenylmercuric acetate, a mercuric compound that is known to activate matrix metalloproteinases, up-regulated ICAM-1 shedding. TIMP-3 (but not TIMP-1 or -2) effectively blocked cleavage. This profile suggests the involvement of the ADAM family of proteases in the cleavage of ICAM-1. The introduction of enzymatically active tumor necrosis factor-alpha-converting enzyme (TACE) into ICAM-1-expressing cells up-regulated cleavage. Small interfering RNA directed against TACE blocked ICAM-1 cleavage. ICAM-1 transfected into TACE-/- fibroblasts did not show increased shedding over constitutive levels in the presence of PMA, whereas cleavage did occur in ICAM-1-transfected TACE+/+ cells. These results indicate that ICAM-1 shedding is mediated by TACE. Blocking the shedding of ICAM-1 altered the cell adhesive function, as ICAM-1-mediated cell adhesion was up-regulated in the presence of TACE small interfering RNA and TIMP-3, but not TIMP-1. However, cleavage was found to occur at multiple sites within the stalk domain of ICAM-1, and numerous point mutations within the region did not affect cleavage, indicating that TACE-mediated cleavage of ICAM-1 may not be sequence-specific.
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Affiliation(s)
- Nina L Tsakadze
- Department of Physiology and Biophysics, University of Louisville, Louisville, Kentucky 40292, USA
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Caron A, Desrosiers RR, Béliveau R. Ischemia injury alters endothelial cell properties of kidney cortex: stimulation of MMP-9. Exp Cell Res 2005; 310:105-16. [PMID: 16112109 DOI: 10.1016/j.yexcr.2005.07.004] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2005] [Revised: 06/15/2005] [Accepted: 07/09/2005] [Indexed: 11/16/2022]
Abstract
Although ischemia is the leading cause of acute renal failure in human, there is little information on the remodeling the kidney endothelium matrix during ischemic injury. In this study, we investigated the activity and expression of MMP-2 and MMP-9, in an isolated endothelial fraction following an acute in vivo reversible ischemia induced in rats by vascular clamping. Ischemia increased serum creatinine levels 1.4-fold, hallmark of acute renal failure. Isolation of the endothelial cell fraction was performed by affinity chromatography using an anti-PECAM-1 antibody. The isolated fraction was assessed by Western blotting analysis of endothelial cell markers. The positively selected fractions were enriched in the endothelial markers eNOS and PECAM-1 by 128-fold and 44-fold, respectively. Gelatin zymography showed that ischemia strongly stimulated proteolytic activity of proMMP-2 (1.8-fold), proMMP-9 (3-fold) and MMP-9 (4-fold) in the endothelial fractions. Western blot analysis indicated that TIMP-2 protein level increased by 3.2-fold in the endothelial fractions during ischemia. Surprisingly, TIMP-1 was absent from the endothelial preparations but was easily detected in the non-endothelial cells. Levels of the endocytic receptor LRP were increased by 2-fold during ischemia in the endothelial fractions. Occludin, a known in vivo MMP-9 substrate, was partly degraded in the endothelial fractions during ischemia, suggesting that the MMP-9 which was upregulated during ischemia was functional. These data suggest that ischemia in kidney could lead to the degradation of the vascular basement membrane and to increased permeability. This suggests new therapeutic approaches for ischemic pathologies by targeting MMP-9 and its regulators.
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Affiliation(s)
- Annick Caron
- Laboratoire de médecine moléculaire, Centre de cancérologie Charles Bruneau, Hôpital Ste-Justine, Université du Québec à Montréal, C.P. 8888, Succursale Centre-Ville, Montréal, Québec, Canada H3C 3P8
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