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Leung J, Qu L, Ye Q, Zhong Z. The immune duality of osteopontin and its therapeutic implications for kidney transplantation. Front Immunol 2025; 16:1520777. [PMID: 40093009 PMCID: PMC11906708 DOI: 10.3389/fimmu.2025.1520777] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Accepted: 02/10/2025] [Indexed: 03/19/2025] Open
Abstract
Osteopontin (OPN) is a multifunctional glycoprotein with various structural domains that enable it to perform diverse functions in both physiological and pathological states. This review comprehensively examines OPN from multiple perspectives, including its protein structure, interactions with receptors, interactions with immune cells, and roles in kidney diseases and transplantation. This review explores the immunological duality of OPN and its significance and value as a biomarker and therapeutic target in kidney transplantation. In cancer, OPN typically promotes tumor evasion by suppressing the immune system. Conversely, in immune-related kidney diseases, particularly kidney transplantation, OPN activates the immune system by enhancing the migration and activation of immune cells, thereby exacerbating kidney damage. This immunological duality may stem from different OPN splice variants and the exposure, after cleavage, of different structural domains, which play distinct biological roles in cellular interactions. Additionally, OPN has a significant biological impact posttransplantation and on chronic kidney disease and, highlighting its importance as a biomarker and potential therapeutic target. Future research should further explore the specific mechanisms of OPN in kidney transplantation to improve treatment strategies and enhance patient quality of life.
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Affiliation(s)
- Junto Leung
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, National Quality Control Center for Donated Organ Procurement, Hubei Key Laboratory of Medical Technology on Transplantation, Hubei Provincial Clinical Research Center for Natural Polymer Biological Liver, Wuhan, Hubei, China
| | - Lei Qu
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, National Quality Control Center for Donated Organ Procurement, Hubei Key Laboratory of Medical Technology on Transplantation, Hubei Provincial Clinical Research Center for Natural Polymer Biological Liver, Wuhan, Hubei, China
| | - Qifa Ye
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, National Quality Control Center for Donated Organ Procurement, Hubei Key Laboratory of Medical Technology on Transplantation, Hubei Provincial Clinical Research Center for Natural Polymer Biological Liver, Wuhan, Hubei, China
- The 3rd Xiangya Hospital of Central South University, NHC Key Laboratory of Translational Research on Transplantation Medicine, Changsha, China
| | - Zibiao Zhong
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, National Quality Control Center for Donated Organ Procurement, Hubei Key Laboratory of Medical Technology on Transplantation, Hubei Provincial Clinical Research Center for Natural Polymer Biological Liver, Wuhan, Hubei, China
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Tanida T, Tagami T, Yanagawa Y, Katagiri S. Identification of an osteopontin structural element for the restoration of a normal endometrial epidermal growth factor (EGF) profile determined by the EGF concentration on day 3 of estrous cycle and pregnancy outcome in repeat breeder dairy cows. Theriogenology 2025; 231:171-181. [PMID: 39461022 DOI: 10.1016/j.theriogenology.2024.10.013] [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: 06/26/2024] [Revised: 10/15/2024] [Accepted: 10/16/2024] [Indexed: 10/29/2024]
Abstract
The loss of a cyclic change with two peaks of increased endometrial epidermal growth factor (EGF) concentration on days 2-4 and 13-14 during the estrous cycle has been linked to low fertility in repeat breeder (RB) cows. We have shown that an intravaginal infusion of osteopontin (OPN) restored the EGF profile in RB cows. The present study aimed to determine a structural element of OPN to restore the normal EGF profile and fertility. Holstein RB cows were diagnosed the EGF profile by a single examination of the endometrial EGF concentration on day 3 of the estrous cycle. Those with an altered EGF profile were intravaginally infused with OPN and its fragments on the day of insemination (day 0); the concentration of endometrial EGF was measured on day 3, and pregnancy was diagnosed on days 30-35. In Study 1, recombinant OPN (rOPN) (16 nmol), thrombin-cleaved N- and C-terminal fragments of rOPN (N-rOPN and C-rOPN, respectively), and a combination of these fragments (Th-rOPN) were infused (n = 13-20). The restoration rate of the normal EGF profile of the N-rOPN group (25.0 %) was a level in between the C-rOPN group (7.7 %) and both the rOPN (55.6 %) and Th-rOPN (64.3 %) groups. In Study 2, PBS (n = 47), rOPN (9.5 nmol, n = 83), and peptides of integrin binding motifs, GRGDSVAYGLK (peptide 1; 32, 320, and 1600 nmol), GRGDS (peptide 2; 320 and 1600 nmol), and SVAYGLK (peptide 3; 320 and 1600 nmol), were infused (n = 20-25). Restoration rates of the normal EGF profile of peptide 1 (320 and 1600 nmol) and peptide 3 (1600 nmol) groups (44.0-56.3 %) were comparable with those of the rOPN group (63.9 %) and higher than those of the PBS group (15.6 %). Restoration rates of the other groups were similar to those of the PBS group. Additional cows received infusions to determine the effect on fertility. Conception rates of the peptide 1 (320 and 1600 nmol; n = 50 each), peptide 3 (1600 nmol; n = 55), and rOPN (n = 111) groups (41.8-50.0 %) were comparable and higher than that of the PBS group (21.6 %, n = 75). In Study 3, PBS (n = 24), peptide 1 (320 nmol; n = 78), and GRGESVAYGLK peptide (peptide 4; 320 and 1600 nmol; n = 50 and 26, respectively) were infused. Restoration rates of the normal EGF profile of peptide 4 and PBS groups (16.0-19.2 %) were comparable and lower than those of the peptide 1 group (44.9 %). Thus, the SVAYGLK motif may be an OPN structural element to restore the normal EGF profile and fertility in RB cows, and the RGD motif may enhance its effect.
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Affiliation(s)
- Takashi Tanida
- Laboratory of Theriogenology, Department of Clinical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, 060-0818, Japan
| | - Takayoshi Tagami
- Laboratory of Molecular Enzymology, Research Faculty of Agriculture, Hokkaido University, Sapporo, 060-8589, Japan
| | - Yojiro Yanagawa
- Laboratory of Theriogenology, Department of Clinical Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, 060-0818, Japan
| | - Seiji Katagiri
- Laboratory of Theriogenology, Department of Clinical Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, 060-0818, Japan.
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Zhao Y, Chen C, Chen K, Sun Y, He N, Zhang X, Xu J, Shen A, Zhao S. Multi-omics analysis of macrophage-associated receptor and ligand reveals a strong prognostic signature and subtypes in hepatocellular carcinoma. Sci Rep 2024; 14:12163. [PMID: 38806553 PMCID: PMC11133315 DOI: 10.1038/s41598-024-62668-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Accepted: 05/20/2024] [Indexed: 05/30/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a significant contributor to morbidity and mortality worldwide. The interaction between receptors and ligands is the primary mode of intercellular signaling and plays a vital role in the progression of HCC. This study aimed to identify the macrophage-related receptor ligand marker genes associated with HCC and further explored the molecular immune mechanisms attributed to altered biomarkers. Single-cell RNA sequencing data containing primary and recurrent samples were downloaded from the China National GeneBank. Cell types were first identified to explore differences between immune cells from different sample sources. CellChat analysis was used to infer and analyze intercellular communication networks quantitatively. Three molecular subtypes were constructed based on the screened twenty macrophage-associated receptor ligand genes. Bulk RNA-Seq data were downloaded from The Cancer Genome Atlas and Gene Expression Omnibus databases. After the screening, the minor absolute shrinkage and selection operator (LASSO) regression model was employed to identify key markers. After collecting peripheral blood and clinical information from patients, an enzyme-linked immunosorbent assay (ELISA) was used to detect the correlation between key markers and IL-10, one of the macrophage markers. After developing a new HCC risk adjustment model and conducting analysis, it was found that there were significant differences in immune status and gene mutations between the high-risk and low-risk groups of patients based on macrophage-associated receptor and ligand genes. This study identified SPP1, ANGPT2, and NCL as key biological targets for HCC. The drug-gene interaction network analysis identified wortmannin, ribavirin, and tarnafloxin as potential therapeutic drugs for the three key markers. In a clinical cohort study, patients with immune checkpoint inhibitor (ICI) resistance had significantly higher expression levels of OPN, ANGPT2, NCL, and IL-10 than patients with ICI-responsiveness. These three key markers were positively correlated with the expression level of IL-10. The signature based on macrophage-associated receptor and ligand genes can accurately predict the prognosis of patients with HCC and the sensitivity to immunotherapy. These results may help guide the development of targeted prevention and personalized treatment of HCC.
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Affiliation(s)
- Yulou Zhao
- Department of Interventional and Vascular Surgery, Affiliated Hospital of Nantong University, Nantong, China
- Medical School, Nantong University, Nantong, China
| | - Cong Chen
- Department of Interventional and Vascular Surgery, Affiliated Hospital of Nantong University, Nantong, China
| | - Kang Chen
- Department of Interventional and Vascular Surgery, Affiliated Hospital of Nantong University, Nantong, China
| | - Yanjun Sun
- The Sixth People's Hospital of Yancheng City, Yancheng, China
| | - Ning He
- Department of Interventional and Vascular Surgery, Affiliated Hospital of Nantong University, Nantong, China
| | - Xiubing Zhang
- Department of Medical Oncology, Nantong Second People's Affiliated Hospital of Nantong University, Nantong, China
| | - Jian Xu
- Department of Medical Oncology, Nantong Second People's Affiliated Hospital of Nantong University, Nantong, China
| | - Aiguo Shen
- Cancer Research Center Nantong, Affiliated Tumor Hospital of Nantong University, Nantong, China.
| | - Suming Zhao
- Department of Interventional and Vascular Surgery, Affiliated Hospital of Nantong University, Nantong, China.
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Wang L, Niu X. Immunoregulatory Roles of Osteopontin in Diseases. Nutrients 2024; 16:312. [PMID: 38276550 PMCID: PMC10819284 DOI: 10.3390/nu16020312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Revised: 01/07/2024] [Accepted: 01/18/2024] [Indexed: 01/27/2024] Open
Abstract
Osteopontin (OPN) is a multifunctional protein that plays a pivotal role in the immune system. It is involved in various biological processes, including cell adhesion, migration and survival. The study of the immunomodulatory effects of OPN is of paramount importance due to its potential therapeutic applications. A comprehensive understanding of how OPN regulates the immune response could pave the way for the development of novel treatments for a multitude of diseases, including autoimmune disorders, infectious diseases and cancer. Therefore, in the following paper, we provide a systematic overview of OPN and its immunoregulatory roles in various diseases, laying the foundation for the development of OPN-based therapies in the future.
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Affiliation(s)
- Lebei Wang
- Department of Immunology and Microbiology, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China;
- College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Xiaoyin Niu
- Department of Immunology and Microbiology, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China;
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Tang Z, Xia Z, Wang X, Liu Y. The critical role of osteopontin (OPN) in fibrotic diseases. Cytokine Growth Factor Rev 2023; 74:86-99. [PMID: 37648616 DOI: 10.1016/j.cytogfr.2023.08.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 08/22/2023] [Accepted: 08/22/2023] [Indexed: 09/01/2023]
Abstract
Fibrosis is a pathological condition characterized by the excessive deposition of extracellular matrix components in tissues and organs, leading to progressive architectural remodelling and contributing to the development of various diseases. Osteopontin (OPN), a highly phosphorylated glycoprotein, has been increasingly recognized for its involvement in the progression of tissue fibrosis. This review provides a comprehensive overview of the genetic and protein structure of OPN and focuses on our current understanding of the role of OPN in the development of fibrosis in the lungs and other tissues. Additionally, special attention is given to the potential of OPN as a biomarker and a novel therapeutic target in the treatment of fibrosis.
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Affiliation(s)
- Ziyi Tang
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu 610041, China; Laboratory of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu 610041, China; Rare Diseases Center, Institute of Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Zijing Xia
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu 610041, China; Laboratory of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu 610041, China; Rare Diseases Center, Institute of Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xiangpeng Wang
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu 610041, China; Department of Rheumatology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100000, China
| | - Yi Liu
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu 610041, China; Laboratory of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu 610041, China; Rare Diseases Center, Institute of Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China.
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Salati NA, Sharma M, Rao NN, Shetty SS, Radhakrishnan RA. Role of osteopontin in oral epithelial dysplasia, oral submucous fibrosis and oral squamous cell carcinoma. J Oral Maxillofac Pathol 2023; 27:706-714. [PMID: 38304518 PMCID: PMC10829450 DOI: 10.4103/jomfp.jomfp_492_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 12/27/2022] [Accepted: 03/06/2023] [Indexed: 02/03/2024] Open
Abstract
Background Inflammatory cells and cytokines in the chronically injured mucosa promote fibrosis in the oral submucous fibrosis (OSF) fibrotic milieu. Osteopontin (OPN) is a wound-healing mediator that upregulates the inflammatory response and is involved in the malignancy and fibrosis of multiple organ systems. Objectives We investigated the expression of OPN in oral potentially malignant disorders (OPMDs) and oral squamous cell carcinomas (OSCCs) to determine its role in the malignant transformation and fibrosis of oral tissues. The expression of OPN in OPMDs and OSCCs was compared and correlated, and the role of OPN as a fibrotic mediator in OSF was explained. Study Design A total of 30 cases of normal mucosa and OPMDs (mild dysplasia, severe dysplasia, OSF and OSCCs) were studied by purposive sampling. In these groups, OPN immunoreactivity was examined and correlated with clinical findings. Results In mild dysplasia, OPN expression was restricted to the basal cell layer with moderate staining intensity. In severe dysplasia, it was extremely intense and extended throughout the epithelium. In the OSF, OPN expression was moderate in the perinuclear areas of the basal cell layer. The expression of OPN was very strong in OSCC. A flow diagram explaining the profibrotic role of OPN in OSF has been provided. Conclusion A positive role of OPN in both pathogenesis and malignant transformation of OPMDs and OSCC has been demonstrated.
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Affiliation(s)
- Nasir A. Salati
- Department of Oral and Maxillofacial Pathology, Dr. Ziauddin Ahmad Dental College, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
| | - Mohit Sharma
- Department of Oral Pathology, SGT Dental College Hospital and Research Institute, Gurugram, Haryana, India
| | - Nirmala N. Rao
- Former Dean, Manipal College of Dental Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Smitha S. Shetty
- Department of Oral Pathology, Manipal College of Dental Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Raghu A. Radhakrishnan
- Department of Oral Pathology, Manipal College of Dental Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
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Hu HJ, Xiao XR, Li T, Liu DM, Geng X, Han M, Cui W. Integrin beta 3-overexpressing mesenchymal stromal cells display enhanced homing and can reduce atherosclerotic plaque. World J Stem Cells 2023; 15:931-946. [PMID: 37900938 PMCID: PMC10600744 DOI: 10.4252/wjsc.v15.i9.931] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 06/22/2023] [Accepted: 08/23/2023] [Indexed: 09/25/2023] Open
Abstract
BACKGROUND Umbilical cord (UC) mesenchymal stem cell (MSC) transplantation is a potential therapeutic intervention for atherosclerotic vascular disease. Integrin beta 3 (ITGB3) promotes cell migration in several cell types. However, whether ITGB-modified MSCs can migrate to plaque sites in vivo and play an anti-atherosclerotic role remains unclear. AIM To investigate whether ITGB3-overexpressing MSCs (MSCsITGB3) would exhibit improved homing efficacy in atherosclerosis. METHODS UC MSCs were isolated and expanded. Lentiviral vectors encoding ITGB3 or green fluorescent protein (GFP) as control were transfected into MSCs. Sixty male apolipoprotein E-/- mice were acquired from Beijing Vital River Lab Animal Technology Co., Ltd and fed with a high-fat diet (HFD) for 12 wk to induce the formation of atherosclerotic lesions. These HFD-fed mice were randomly separated into three clusters. GFP-labeled MSCs (MSCsGFP) or MSCsITGB3 were transplanted into the mice intravenously via the tail vein. Immunofluorescence staining, Oil red O staining, histological analyses, western blotting, enzyme-linked immunosorbent assay, and quantitative real-time polymerase chain reaction were used for the analyses. RESULTS ITGB3 modified MSCs successfully differentiated into the "osteocyte" and "adipocyte" phenotypes and were characterized by positive expression (> 91.3%) of CD29, CD73, and CD105 and negative expression (< 1.35%) of CD34 and Human Leukocyte Antigen-DR. In a transwell assay, MSCsITGB3 showed significantly faster migration than MSCsGFP. ITGB3 overexpression had no effects on MSC viability, differentiation, and secretion. Immunofluorescence staining revealed that ITGB3 overexpression substantially enhanced the homing of MSCs to plaque sites. Oil red O staining and histological analyses further confirmed the therapeutic effects of MSCsITGB3, significantly reducing the plaque area. Enzyme-linked immunosorbent assay and quantitative real-time polymerase chain reaction revealed that MSCITGB3 transplantation considerably decreased the inflammatory response in pathological tissues by improving the dynamic equilibrium of pro- and anti-inflammatory cytokines. CONCLUSION These results showed that ITGB3 overexpression enhanced the MSC homing ability, providing a potential approach for MSC delivery to plaque sites, thereby optimizing their therapeutic effects.
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Affiliation(s)
- Hai-Juan Hu
- First Division, Department of Cardiology, The Second Hospital of Hebei Medical University and Institute of Cardiocerebrovascular Disease of Hebei Province, Shijiazhuang 050000, Hebei Province, China
| | - Xue-Ru Xiao
- Department of Obstetrics, Shijiazhuang People's Hospital, Shijiazhuang 050030, Hebei Province, China
| | - Tong Li
- First Division, Department of Cardiology, The Second Hospital of Hebei Medical University and Institute of Cardiocerebrovascular Disease of Hebei Province, Shijiazhuang 050000, Hebei Province, China
| | - De-Min Liu
- First Division, Department of Cardiology, The Second Hospital of Hebei Medical University and Institute of Cardiocerebrovascular Disease of Hebei Province, Shijiazhuang 050000, Hebei Province, China
| | - Xue Geng
- First Division, Department of Cardiology, The Second Hospital of Hebei Medical University and Institute of Cardiocerebrovascular Disease of Hebei Province, Shijiazhuang 050000, Hebei Province, China
| | - Mei Han
- Key Laboratory of Medical Biotechnology of Hebei Province, Department of Biochemistry and Molecular Biology, College of Basic Medicine, Cardiovascular Medical Science Center, Hebei Medical University, Shijiazhuang 050017, Hebei Province, China
| | - Wei Cui
- First Division, Department of Cardiology, The Second Hospital of Hebei Medical University and Institute of Cardiocerebrovascular Disease of Hebei Province, Shijiazhuang 050000, Hebei Province, China.
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Lin EYH, Xi W, Aggarwal N, Shinohara ML. Osteopontin (OPN)/SPP1: from its biochemistry to biological functions in the innate immune system and the central nervous system (CNS). Int Immunol 2023; 35:171-180. [PMID: 36525591 PMCID: PMC10071791 DOI: 10.1093/intimm/dxac060] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2022] [Accepted: 12/14/2022] [Indexed: 12/23/2022] Open
Abstract
Osteopontin (OPN) is a multifunctional protein, initially identified in osteosarcoma cells with its role of mediating osteoblast adhesion. Later studies revealed that OPN is associated with many inflammatory conditions caused by infections, allergic responses, autoimmunity and tissue damage. Many cell types in the peripheral immune system express OPN with various functions, which could be beneficial or detrimental. Also, more recent studies demonstrated that OPN is highly expressed in the central nervous system (CNS), particularly in microglia during CNS diseases and development. However, understanding of mechanisms underlying OPN's functions in the CNS is still limited. In this review, we focus on peripheral myeloid cells and CNS-resident cells to discuss the expression and functions of OPN.
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Affiliation(s)
- Elliot Yi-Hsin Lin
- Department of Immunology, Duke University School of Medicine, Durham, NC 27710, USA
| | - Wen Xi
- Department of Immunology, Duke University School of Medicine, Durham, NC 27710, USA
| | - Nupur Aggarwal
- Department of Immunology, Duke University School of Medicine, Durham, NC 27710, USA
| | - Mari L Shinohara
- Department of Immunology, Duke University School of Medicine, Durham, NC 27710, USA
- Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710, USA
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Osteopontin: A Bone-Derived Protein Involved in Rheumatoid Arthritis and Osteoarthritis Immunopathology. Biomolecules 2023; 13:biom13030502. [PMID: 36979437 PMCID: PMC10046882 DOI: 10.3390/biom13030502] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 02/24/2023] [Accepted: 03/07/2023] [Indexed: 03/12/2023] Open
Abstract
Osteopontin (OPN) is a bone-derived phosphoglycoprotein related to physiological and pathological mechanisms that nowadays has gained relevance due to its role in the immune system response to chronic degenerative diseases, including rheumatoid arthritis (RA) and osteoarthritis (OA). OPN is an extracellular matrix (ECM) glycoprotein that plays a critical role in bone remodeling. Therefore, it is an effector molecule that promotes joint and cartilage destruction observed in clinical studies, in vitro assays, and animal models of RA and OA. Since OPN undergoes multiple modifications, including posttranslational changes, proteolytic cleavage, and binding to a wide range of receptors, the mechanisms by which it produces its effects, in some cases, remain unclear. Although there is strong evidence that OPN contributes significantly to the immunopathology of RA and OA when considering it as a common denominator molecule, some experimental trial results argue for its protective role in rheumatic diseases. Elucidating in detail OPN involvement in bone and cartilage degeneration is of interest to the field of rheumatology. This review aims to provide evidence of the OPN’s multifaceted role in promoting joint and cartilage destruction and propose it as a common denominator of AR and OA immunopathology.
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Chen K, Wang Q, Liu X, Wang F, Ma Y, Zhang S, Shao Z, Yang Y, Tian X. Single Cell RNA-Seq Identifies Immune-Related Prognostic Model and Key Signature-SPP1 in Pancreatic Ductal Adenocarcinoma. Genes (Basel) 2022; 13:1760. [PMID: 36292645 PMCID: PMC9601640 DOI: 10.3390/genes13101760] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 09/15/2022] [Accepted: 09/26/2022] [Indexed: 11/29/2022] Open
Abstract
There are no reliable biomarkers for early diagnosis or prognosis evaluation in pancreatic ductal adenocarcinoma (PDAC). Multiple scRNA-seq datasets for PDAC were retrieved from online databases and combined with scRNA-seq results from our previous study. The malignant ductal cells were identified through calculating copy number variation (CNV) scores. The robust markers of malignant ductal cells in PDAC were found. Five immune-related signatures, including SPP1, LINC00683, SNHG10, LINC00237, and CASC19, were used to develop a risk score formula to predict the overall survival of PDAC patients. We also constructed an easy-to-use nomogram, combining risk score, N stage, and margin status. The expression level of SPP1 was related to the prognosis and immune regulators. We found that SPP1 was mainly expressed in ductal cells and macrophages in PDAC. In conclusion, we constructed a promising prognostic model based on immune-related signatures for PDAC using scRNA-seq and TCGA_PAAD datasets.
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Affiliation(s)
- Kai Chen
- Department of General Surgery, Peking University First Hospital, Beijing 100034, China
| | - Qi Wang
- Department of General Surgery, Peking University First Hospital, Beijing 100034, China
| | - Xinxin Liu
- Department of General Surgery, Peking University First Hospital, Beijing 100034, China
| | - Feng Wang
- Department of Endoscopy Center, Peking University First Hospital, Beijing 100034, China
| | - Yongsu Ma
- Department of General Surgery, Peking University First Hospital, Beijing 100034, China
| | - Shupeng Zhang
- Department of General Surgery, Tianjin Fifth Centre Hospital, Tianjin 300450, China
| | - Zhijiang Shao
- Department of General Surgery, Tianjin Fifth Centre Hospital, Tianjin 300450, China
| | - Yinmo Yang
- Department of General Surgery, Peking University First Hospital, Beijing 100034, China
| | - Xiaodong Tian
- Department of General Surgery, Peking University First Hospital, Beijing 100034, China
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Aggarwal N, Deerhake ME, DiPalma D, Shahi SK, Gaggioli MR, Mangalam AK, Shinohara ML. Secreted osteopontin from CD4 + T cells limits acute graft-versus-host disease. Cell Rep 2021; 37:110170. [PMID: 34965439 PMCID: PMC8759344 DOI: 10.1016/j.celrep.2021.110170] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Revised: 11/03/2021] [Accepted: 12/03/2021] [Indexed: 11/26/2022] Open
Abstract
Osteopontin (OPN) has been considered a potential biomarker of graft-versus-host disease (GVHD). However, the function of OPN in GVHD is still elusive. Using a mouse model of acute GVHD (aGVHD), we report that OPN generated by CD4+ T cells is sufficient to exert a beneficial effect in controlling aGVHD through limiting gastrointestinal pathology, a major target organ of aGVHD. CD4+ T cell-derived OPN works on CD44 expressed in intestinal epithelial cells (IECs) and abates cell death of IECs. OPN also modulates gut microbiota with enhanced health-associated commensal bacteria Akkermansia. Importantly, we use our in vivo mouse mutant model to specifically express OPN isoforms and demonstrate that secreted OPN (sOPN), not intracellular OPN (iOPN), is solely responsible for the protective role of OPN. This study demonstrates that sOPN generated by CD4+ T cells is potent enough to limit aGVHD.
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Affiliation(s)
- Nupur Aggarwal
- Department of Immunology, Duke University Medical School, Durham, NC 27710, USA
| | | | - Devon DiPalma
- Department of Immunology, Duke University Medical School, Durham, NC 27710, USA
| | - Shailesh K Shahi
- Department of Pathology, University of Iowa, Iowa City, IA 52242, USA
| | - Margaret R Gaggioli
- Department of Molecular Genetics and Microbiology, Duke University Medical School, Durham, NC 27710, USA
| | | | - Mari L Shinohara
- Department of Immunology, Duke University Medical School, Durham, NC 27710, USA; Department of Molecular Genetics and Microbiology, Duke University Medical School, Durham, NC 27710, USA.
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12
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Hattori T, Iwasaki-Hozumi H, Bai G, Chagan-Yasutan H, Shete A, Telan EF, Takahashi A, Ashino Y, Matsuba T. Both Full-Length and Protease-Cleaved Products of Osteopontin Are Elevated in Infectious Diseases. Biomedicines 2021; 9:biomedicines9081006. [PMID: 34440210 PMCID: PMC8394573 DOI: 10.3390/biomedicines9081006] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 08/05/2021] [Accepted: 08/09/2021] [Indexed: 12/13/2022] Open
Abstract
Circulating full-length osteopontin (FL-OPN) is elevated in plasma from patients with various infectious diseases, such as adult T-cell leukemia, Mycobacterium tuberculosis (TB), hepatitis virus infection, leptospirosis, acquired immune deficiency syndrome (AIDS), AIDS/TB, and coronavirus disease 2019 (COVID-19). Proteolysis of OPN by thrombin, matrix metalloproteases, caspase 8/3, cathepsin D, plasmin, and enterokinase generates various cleaved OPNs with a variety of bioactivities by binding to different target cells. Moreover, OPN is susceptible to gradual proteolysis. During inflammation, one of the cleaved fragments, N-terminal thrombin-cleaved OPN (trOPN or OPN-Arg168 [OPN-R]), induces dendritic cell (DC) adhesion. Further cleavage by carboxypeptidase B2 or carboxypeptidase N removes Arg168 from OPN-R to OPN-Leu167 (OPN-L). Consequently, OPN-L decreases DC adhesion. In particular, the differences in plasma level over time are observed between FL-OPN and its cleaved OPNs during inflammation. We found that the undefined OPN levels (mixture of FL-OPN and cleaved OPN) were elevated in plasma and reflected the pathology of TB and COVID-19 rather than FL-OPN. These infections are associated with elevated levels of various proteases. Inhibition of the cleavage or the activities of cleaved products may improve the outcome of the therapy. Research on the metabolism of OPN is expected to create new therapies against infectious diseases.
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Affiliation(s)
- Toshio Hattori
- Research Institute of Health and Welfare, Kibi International University, Takahashi 716-8508, Japan; (H.I.-H.); (G.B.); (H.C.-Y.); (A.T.)
- Correspondence: ; Tel./Fax: +81-866-22-9469
| | - Hiroko Iwasaki-Hozumi
- Research Institute of Health and Welfare, Kibi International University, Takahashi 716-8508, Japan; (H.I.-H.); (G.B.); (H.C.-Y.); (A.T.)
| | - Gaowa Bai
- Research Institute of Health and Welfare, Kibi International University, Takahashi 716-8508, Japan; (H.I.-H.); (G.B.); (H.C.-Y.); (A.T.)
| | - Haorile Chagan-Yasutan
- Research Institute of Health and Welfare, Kibi International University, Takahashi 716-8508, Japan; (H.I.-H.); (G.B.); (H.C.-Y.); (A.T.)
- Mongolian Psychosomatic Medicine Department, International Mongolian Medicine Hospital of Inner Mongolia, Hohhot 010065, China
| | - Ashwnini Shete
- ICMR-National AIDS Research Institute, 73 G-Block, MIDC, Bhosari, Pune 411026, India;
| | - Elizabeth Freda Telan
- STD AIDS Cooperative Central Laboratory, San Lazaro Hospital, Manila 1003, Philippines;
| | - Atsushi Takahashi
- Research Institute of Health and Welfare, Kibi International University, Takahashi 716-8508, Japan; (H.I.-H.); (G.B.); (H.C.-Y.); (A.T.)
| | - Yugo Ashino
- Department of Respiratory Medicine, Sendai City Hospital, Sendai 982-8502, Japan;
| | - Takashi Matsuba
- Department of Animal Pharmaceutical Science, School of Pharmaceutical Science, Kyusyu University of Health and Welfare, Nobeoka 882-8508, Japan;
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13
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Jafari SH, Rabiei N, Taghizadieh M, Mirazimi SMA, Kowsari H, Farzin MA, Razaghi Bahabadi Z, Rezaei S, Mohammadi AH, Alirezaei Z, Dashti F, Nejati M. Joint application of biochemical markers and imaging techniques in the accurate and early detection of glioblastoma. Pathol Res Pract 2021; 224:153528. [PMID: 34171601 DOI: 10.1016/j.prp.2021.153528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Revised: 06/09/2021] [Accepted: 06/14/2021] [Indexed: 11/28/2022]
Abstract
Glioblastoma is a primary brain tumor with the most metastatic effect in adults. Despite the wide range of multidimensional treatments, tumor heterogeneity is one of the main causes of tumor spread and gives great complexity to diagnostic and therapeutic methods. Therefore, featuring noble noninvasive prognostic methods that are focused on glioblastoma heterogeneity is perceived as an urgent need. Imaging neuro-oncological biomarkers including MGMT (O6-methylguanine-DNA methyltransferase) promoter methylation status, tumor grade along with other tumor characteristics and demographic features (e.g., age) are commonly referred to during diagnostic, therapeutic and prognostic processes. Therefore, the use of new noninvasive prognostic methods focused on glioblastoma heterogeneity is considered an urgent need. Some neuronal biomarkers, including the promoter methylation status of the promoter MGMT, the characteristics and grade of the tumor, along with the patient's demographics (such as age and sex) are involved in diagnosis, treatment, and prognosis. Among the wide array of imaging techniques, magnetic resonance imaging combined with the more physiologically detailed technique of H-magnetic resonance spectroscopy can be useful in diagnosing neurological cancer patients. In addition, intracranial tumor qualitative analysis and sometimes tumor biopsies help in accurate diagnosis. This review summarizes the evidence for biochemical biomarkers being a reliable biomarker in the early detection and disease management in GBM. Moreover, we highlight the correlation between Imaging techniques and biochemical biomarkers and ask whether they can be combined.
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Affiliation(s)
- Seyed Hamed Jafari
- Medical Imaging Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Nikta Rabiei
- School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad Taghizadieh
- Department of Pathology, School of Medicine, Center for Women's Health Research Zahra, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sayad Mohammad Ali Mirazimi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran; Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Hamed Kowsari
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran; Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Mohammad Amin Farzin
- Department of Laboratory Medicine, School of Allied Medical Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Zahra Razaghi Bahabadi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran; Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Samaneh Rezaei
- Department of Medical Biotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amir Hossein Mohammadi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Zahra Alirezaei
- Department of Medical Physics, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran; Paramedical School, Bushehr University of Medical Sciences, Bushehr, Iran.
| | - Fatemeh Dashti
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran; Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran.
| | - Majid Nejati
- Anatomical Sciences Research Center, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
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14
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Song Z, Chen W, Athavale D, Ge X, Desert R, Das S, Han H, Nieto N. Osteopontin Takes Center Stage in Chronic Liver Disease. Hepatology 2021; 73:1594-1608. [PMID: 32986864 PMCID: PMC8106357 DOI: 10.1002/hep.31582] [Citation(s) in RCA: 111] [Impact Index Per Article: 27.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 08/25/2020] [Accepted: 09/09/2020] [Indexed: 12/13/2022]
Abstract
Osteopontin (OPN) was first identified in 1986. The prefix osteo- means bone; however, OPN is expressed in other tissues, including liver. The suffix -pontin means bridge and denotes the role of OPN as a link protein within the extracellular matrix. While OPN has well-established physiological roles, multiple "omics" analyses suggest that it is also involved in chronic liver disease. In this review, we provide a summary of the OPN gene and protein structure and regulation. We outline the current knowledge on how OPN is involved in hepatic steatosis in the context of alcoholic liver disease and non-alcoholic fatty liver disease. We describe the mechanisms whereby OPN participates in inflammation and liver fibrosis and discuss current research on its role in hepatocellular carcinoma and cholangiopathies. To conclude, we highlight important points to consider when doing research on OPN and provide direction for making progress on how OPN contributes to chronic liver disease.
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Affiliation(s)
- Zhuolun Song
- Department of Pathology, University of Illinois at Chicago, Chicago, IL
| | - Wei Chen
- Department of Pathology, University of Illinois at Chicago, Chicago, IL
| | - Dipti Athavale
- Department of Pathology, University of Illinois at Chicago, Chicago, IL
| | - Xiaodong Ge
- Department of Pathology, University of Illinois at Chicago, Chicago, IL
| | - Romain Desert
- Department of Pathology, University of Illinois at Chicago, Chicago, IL
| | - Sukanta Das
- Department of Pathology, University of Illinois at Chicago, Chicago, IL
| | - Hui Han
- Department of Pathology, University of Illinois at Chicago, Chicago, IL
| | - Natalia Nieto
- Department of Pathology, University of Illinois at Chicago, Chicago, IL,Department of Medicine, Division of Gastroenterology and Hepatology, University of Illinois at Chicago, Chicago, IL
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15
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Carvalho MS, Cabral JMS, da Silva CL, Vashishth D. Bone Matrix Non-Collagenous Proteins in Tissue Engineering: Creating New Bone by Mimicking the Extracellular Matrix. Polymers (Basel) 2021; 13:polym13071095. [PMID: 33808184 PMCID: PMC8036283 DOI: 10.3390/polym13071095] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 03/18/2021] [Accepted: 03/20/2021] [Indexed: 02/06/2023] Open
Abstract
Engineering biomaterials that mimic the extracellular matrix (ECM) of bone is of significant importance since most of the outstanding properties of the bone are due to matrix constitution. Bone ECM is composed of a mineral part comprising hydroxyapatite and of an organic part of primarily collagen with the rest consisting on non-collagenous proteins. Collagen has already been described as critical for bone tissue regeneration; however, little is known about the potential effect of non-collagenous proteins on osteogenic differentiation, even though these proteins were identified some decades ago. Aiming to engineer new bone tissue, peptide-incorporated biomimetic materials have been developed, presenting improved biomaterial performance. These promising results led to ongoing research focused on incorporating non-collagenous proteins from bone matrix to enhance the properties of the scaffolds namely in what concerns cell migration, proliferation, and differentiation, with the ultimate goal of designing novel strategies that mimic the native bone ECM for bone tissue engineering applications. Overall, this review will provide an overview of the several non-collagenous proteins present in bone ECM, their functionality and their recent applications in the bone tissue (including dental) engineering field.
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Affiliation(s)
- Marta S. Carvalho
- Center for Biotechnology and Interdisciplinary Studies, Department of Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, NY 12180, USA
- Department of Bioengineering and iBB—Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, 1049-001 Lisboa, Portugal; (J.M.S.C.); (C.L.d.S.)
- Associate Laboratory i4HB—Institute for Health and Bioeconomy, Instituto Superior Técnico, Universidade de Lisboa, 1049-001 Lisboa, Portugal
- Correspondence: (M.S.C.); (D.V.)
| | - Joaquim M. S. Cabral
- Department of Bioengineering and iBB—Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, 1049-001 Lisboa, Portugal; (J.M.S.C.); (C.L.d.S.)
- Associate Laboratory i4HB—Institute for Health and Bioeconomy, Instituto Superior Técnico, Universidade de Lisboa, 1049-001 Lisboa, Portugal
| | - Cláudia L. da Silva
- Department of Bioengineering and iBB—Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, 1049-001 Lisboa, Portugal; (J.M.S.C.); (C.L.d.S.)
- Associate Laboratory i4HB—Institute for Health and Bioeconomy, Instituto Superior Técnico, Universidade de Lisboa, 1049-001 Lisboa, Portugal
| | - Deepak Vashishth
- Center for Biotechnology and Interdisciplinary Studies, Department of Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, NY 12180, USA
- Correspondence: (M.S.C.); (D.V.)
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16
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Hamada Y, Tanaka S, Fujishita Y, Cho JS, Usuki T, Yokoyama Y, Wu X, Mori S, Yamamoto H, Kogo M. The synthetic peptide SVVYGLR promotes myogenic cell motility via the TGFβ1/Smad signaling pathway and facilitates skeletal myogenic differentiation in vitro. Dent Mater J 2021; 40:957-963. [PMID: 33716279 DOI: 10.4012/dmj.2020-354] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
In the present study, we investigated the possible involvement of the TGF-β/Smad signaling pathway in the osteopontin-derived SVVYGLR (SV) peptide-mediated migratory activities of myogenic cells and evaluated the facilitative effects of the SV peptide on the differentiation of myogenic cells in vitro. The SV peptide-induced migration in both human-derived satellite cells and myoblasts was substantially suppressed by the TGF-β1 receptor inhibitor SB431542 or SB505124. Besides, the expression level of the Smad3 phosphorylation was further enhanced by the addition of the SV peptide in comparison with control groups. Furthermore, an increase in the expression of myogenin-positive nuclei and a higher number of nascent myotubes with myosin heavy chain expression was confirmed in cultured myoblasts supplemented with the SV peptide. These results suggest that the involvement of the TGF-β/Smad signaling pathway in the SV peptide-mediated migration and the facilitative effect of the SV peptide on the differentiation of myogenic cells into myotubes.
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Affiliation(s)
- Yoshinosuke Hamada
- Department of Molecular Pathology, Division of Health Sciences, Graduate School of Medicine, Osaka University.,Department of Health Economics and Management, Graduate School of Medicine, Osaka University.,Department of Pediatric Dentistry, Osaka Dental University
| | - Susumu Tanaka
- The 1st Department of Oral and Maxillofacial Surgery, Graduate School of Dentistry, Osaka University
| | - Yohei Fujishita
- The 1st Department of Oral and Maxillofacial Surgery, Graduate School of Dentistry, Osaka University
| | - Jung-Soo Cho
- The 1st Department of Oral and Maxillofacial Surgery, Graduate School of Dentistry, Osaka University
| | - Takasuke Usuki
- The 1st Department of Oral and Maxillofacial Surgery, Graduate School of Dentistry, Osaka University
| | - Yuhki Yokoyama
- Department of Molecular Pathology, Division of Health Sciences, Graduate School of Medicine, Osaka University
| | - Xin Wu
- Department of Molecular Pathology, Division of Health Sciences, Graduate School of Medicine, Osaka University
| | - Seiji Mori
- Department of Molecular Pathology, Division of Health Sciences, Graduate School of Medicine, Osaka University.,Department of Medical Technology, Faculty of Health Sciences, Morinomiya University of Medical Sciences
| | - Hirofumi Yamamoto
- Department of Molecular Pathology, Division of Health Sciences, Graduate School of Medicine, Osaka University
| | - Mikihiko Kogo
- The 1st Department of Oral and Maxillofacial Surgery, Graduate School of Dentistry, Osaka University
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17
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Zhao J, Feng Y. Surface Engineering of Cardiovascular Devices for Improved Hemocompatibility and Rapid Endothelialization. Adv Healthc Mater 2020; 9:e2000920. [PMID: 32833323 DOI: 10.1002/adhm.202000920] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Revised: 07/18/2020] [Indexed: 12/13/2022]
Abstract
Cardiovascular devices have been widely applied in the clinical treatment of cardiovascular diseases. However, poor hemocompatibility and slow endothelialization on their surface still exist. Numerous surface engineering strategies have mainly sought to modify the device surface through physical, chemical, and biological approaches to improve surface hemocompatibility and endothelialization. The alteration of physical characteristics and pattern topographies brings some hopeful outcomes and plays a notable role in this respect. The chemical and biological approaches can provide potential signs of success in the endothelialization of vascular device surfaces. They usually involve therapeutic drugs, specific peptides, adhesive proteins, antibodies, growth factors and nitric oxide (NO) donors. The gene engineering can enhance the proliferation, growth, and migration of vascular cells, thus boosting the endothelialization. In this review, the surface engineering strategies are highlighted and summarized to improve hemocompatibility and rapid endothelialization on the cardiovascular devices. The potential outlook is also briefly discussed to help guide endothelialization strategies and inspire further innovations. It is hoped that this review can assist with the surface engineering of cardiovascular devices and promote future advancements in this emerging research field.
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Affiliation(s)
- Jing Zhao
- School of Chemical Engineering and Technology Tianjin University Yaguan Road 135 Tianjin 300350 P. R. China
| | - Yakai Feng
- School of Chemical Engineering and Technology Tianjin University Yaguan Road 135 Tianjin 300350 P. R. China
- Collaborative Innovation Center of Chemical Science and Chemical Engineering (Tianjin) Yaguan Road 135 Tianjin 300350 P. R. China
- Key Laboratory of Systems Bioengineering (Ministry of Education) Tianjin University Tianjin 300072 P. R. China
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18
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Neutralizing antibody against osteopontin attenuates non-alcoholic steatohepatitis in mice. J Cell Commun Signal 2020; 14:223-232. [PMID: 32062834 DOI: 10.1007/s12079-020-00554-7] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Accepted: 02/13/2020] [Indexed: 12/14/2022] Open
Abstract
Previously, we reported that an extracellular matrix protein, osteopontin (OPN), is involved in various autoimmune diseases using a neutralizing polyclonal antibody against OPN generated in rabbits. However, the antibody cannot be used for long-term mouse models of chronic inflammatory disease because of the induction of antibodies against anti-OPN rabbit IgG. In this study, we generated a new antibody, anti-mouse OPN mouse IgG (35B6). 35B6 inhibited the cell adhesion of mouse and human OPN to Chinese Hamster Ovary (CHO) cells or CHO cells expressing α4 or α9 integrin. It was reported that OPN is highly expressed and has an important role in a chronic liver disease, non-alcoholic steatohepatitis (NASH). 35B6 injection twice a week for 8 weeks attenuated liver inflammation and fibrosis in a NASH mouse model, suggesting 35B6 is beneficial for the treatment of NASH. 35B6 was preferable to the rabbit anti-OPN antibody for investigating the in vivo function of OPN in mouse models of long-term disease.
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19
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Matsumoto H, Kohara R, Sugi M, Usui A, Oyama K, Mannen H, Sasazaki S. The non-synonymous mutation in bovine SPP1 gene influences carcass weight. Heliyon 2019; 5:e03006. [PMID: 31879711 PMCID: PMC6920195 DOI: 10.1016/j.heliyon.2019.e03006] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Revised: 09/12/2019] [Accepted: 12/05/2019] [Indexed: 01/12/2023] Open
Abstract
Meat quality in beef cattle is controlled by genetic factors. SPP1 (secreted phosphoprotein 1) gene, coding a multifunctional cytokine with diverse biological functions, is the candidate gene influencing carcass traits. In this study, we tried to discover DNA polymorphisms associated with beef quality in bovine SPP1 gene, so that two SNPs (single nucleotide polymorphisms) in the promoter region and one SNP in the CDS (coding sequence) region were identified. Although the formers were predicted to alter SPP1 expression, they did not show any effects on the traits. On the contrary, statistical analysis revealed that g.58675C > T, a non-synonymous mutation from threonine to methionine in the conservative region, had a significant effect on carcass weight. Carcass weight of the animals with C/T allele (473.9 ± 6.0 kg) was significantly heavier than that of the C/C homozygotes (459.2 ± 2.8 kg). Because SPP1 gene functions in skeletal muscle cells as a positive regulator, the non-synonymous mutation might influence muscle development and remodeling, resulting in increased carcass weight of the C/T animals. Our results indicate that the SNP can be applied as a DNA marker for the improvement of beef cattle.
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Affiliation(s)
- Hirokazu Matsumoto
- Laboratory of Animal Genetics, Faculty of Agriculture, Tokai University, Kumamoto, 862-8652, Japan
| | - Ryosuke Kohara
- Laboratory of Animal Genetics, Faculty of Agriculture, Tokai University, Kumamoto, 862-8652, Japan
| | - Makoto Sugi
- Laboratory of Animal Genetics, Faculty of Agriculture, Tokai University, Kumamoto, 862-8652, Japan
| | - Azumi Usui
- Laboratory of Animal Genetics, Faculty of Agriculture, Tokai University, Kumamoto, 862-8652, Japan
| | - Kenji Oyama
- Food Resources Education and Research Center, Graduate School of Agricultural Science, Kobe University, Kasai, Hyogo, 675-2103, Japan
| | - Hideyuki Mannen
- Laboratory of Animal Breeding and Genetics, Graduate School of Agricultural Science, Kobe University, Kobe, 657-8501, Japan
| | - Shinji Sasazaki
- Laboratory of Animal Breeding and Genetics, Graduate School of Agricultural Science, Kobe University, Kobe, 657-8501, Japan
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20
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Kramerova I, Kumagai-Cresse C, Ermolova N, Mokhonova E, Marinov M, Capote J, Becerra D, Quattrocelli M, Crosbie RH, Welch E, McNally EM, Spencer MJ. Spp1 (osteopontin) promotes TGFβ processing in fibroblasts of dystrophin-deficient muscles through matrix metalloproteinases. Hum Mol Genet 2019; 28:3431-3442. [PMID: 31411676 PMCID: PMC7345878 DOI: 10.1093/hmg/ddz181] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Revised: 07/15/2019] [Accepted: 07/18/2019] [Indexed: 12/20/2022] Open
Abstract
Duchenne muscular dystrophy (DMD) is caused by mutations in the gene encoding dystrophin. Prior work has shown that DMD progression can vary, depending on the genetic makeup of the patient. Several modifier alleles have been identified including LTBP4 and SPP1. We previously showed that Spp1 exacerbates the DMD phenotype in the mdx mouse model by promoting fibrosis and by skewing macrophage polarization. Here, we studied the mechanisms involved in Spp1's promotion of fibrosis by using both isolated fibroblasts and genetically modified mice. We found that Spp1 upregulates collagen expression in mdx fibroblasts by enhancing TGFβ signaling. Spp1's effects on TGFβ signaling are through induction of MMP9 expression. MMP9 is a protease that can release active TGFβ ligand from its latent complex. In support for activation of this pathway in our model, we showed that treatment of mdx fibroblasts with MMP9 inhibitor led to accumulation of the TGFβ latent complex, decreased levels of active TGFβ and reduced collagen expression. Correspondingly, we found reduced active TGFβ in Spp1-/-mdxB10 and Mmp9-/-mdxB10 muscles in vivo. Taken together with previous observations of reduced fibrosis in both models, these data suggest that Spp1 acts upstream of TGFβ to promote fibrosis in mdx muscles. We found that in the context of constitutively upregulated TGFβ signaling (such as in the mdxD2 model), ablation of Spp1 has very little effect on fibrosis. Finally, we performed proof-of-concept studies showing that postnatal pharmacological inhibition of Spp1 reduces fibrosis and improves muscle function in mdx mice.
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Affiliation(s)
- Irina Kramerova
- Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles
| | - Chino Kumagai-Cresse
- Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles
- Center for Genetic Medicine, Northwestern University Feinberg School of Medicine
| | - Natalia Ermolova
- Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles
| | - Ekaterina Mokhonova
- Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles
| | - Masha Marinov
- Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles
| | - Joana Capote
- Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles
- Molecular, Cellular and Integrative Physiology, University of California, Los Angeles
| | - Diana Becerra
- Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles
| | - Mattia Quattrocelli
- Center for Genetic Medicine, Northwestern University Feinberg School of Medicine
| | - Rachelle H Crosbie
- Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles
- Department of Integrative Biology and Physiology, University of California, Los Angeles
- Paul Wellstone Muscular Dystrophy Center
| | | | - Elizabeth M McNally
- Center for Genetic Medicine, Northwestern University Feinberg School of Medicine
- Paul Wellstone Muscular Dystrophy Center
| | - Melissa J Spencer
- Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles
- Paul Wellstone Muscular Dystrophy Center
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21
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Carvalho MS, Cabral JM, da Silva CL, Vashishth D. Synergistic effect of extracellularly supplemented osteopontin and osteocalcin on stem cell proliferation, osteogenic differentiation, and angiogenic properties. J Cell Biochem 2018; 120:6555-6569. [PMID: 30362184 DOI: 10.1002/jcb.27948] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Accepted: 10/02/2018] [Indexed: 12/17/2022]
Abstract
A high demand for functional bone grafts is being observed worldwide, especially due to the increased life expectancy. Osteoinductive components should be incorporated into functional bone grafts, accelerating cell recruitment, cell proliferation, angiogenesis, and new bone formation at a defect site. Noncollagenous bone matrix proteins, especially osteopontin (OPN) and osteocalcin (OC), have been reported to regulate some physiological process, such as cell migration and bone mineralization. However, the effects of OPN and OC on cell proliferation, osteogenic differentiation, mineralization, and angiogenesis are still undefined. Therefore, we assessed the exogenous effect of OPN and OC supplementation on human bone marrow mesenchymal stem/stromal cells (hBM MSC) proliferation and osteogenic differentiation. OPN dose-dependently increased the proliferation of hBM MSC, as well as improved the angiogenic properties of human umbilical vein endothelial cells (HUVEC) by increasing the capillary-like tube formation in vitro. On the other hand, OC enhanced the differentiation of hBM MSC into osteoblasts and demonstrated an increase in extracellular calcium levels and alkaline phosphatase activity, as well as higher messenger RNA levels of mature osteogenic markers osteopontin and osteocalcin. In vivo assessment of OC/OPN-enhanced scaffolds in a critical-sized defect rabbit long-bone model revealed no infection, while new bone was being formed. Taken together, these results suggest that OC and OPN stimulate bone regeneration by inducing stem cell proliferation, osteogenesis and by enhancing angiogenic properties. The synergistic effect of OC and OPN observed in this study can be applied as an attractive strategy for bone regeneration therapeutics by targeting different vital cellular processes.
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Affiliation(s)
- Marta S Carvalho
- Department of Biomedical Engineering, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York.,Department of Bioengineering, iBB - Institute of Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal
| | - Joaquim Ms Cabral
- Department of Bioengineering, iBB - Institute of Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal.,The Discoveries Centre for Regenerative and Precision Medicine, Lisbon Campus, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal
| | - Cláudia L da Silva
- Department of Bioengineering, iBB - Institute of Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal.,The Discoveries Centre for Regenerative and Precision Medicine, Lisbon Campus, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal
| | - Deepak Vashishth
- Department of Biomedical Engineering, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York
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Biomarkers identification for PML monitoring, during Natalizumab (Tysabri®) treatment in Relapsing-Remitting Multiple Sclerosis. Mult Scler Relat Disord 2018; 20:93-99. [DOI: 10.1016/j.msard.2018.01.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2017] [Revised: 12/31/2017] [Accepted: 01/12/2018] [Indexed: 12/19/2022]
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Proangiogenic functions of an RGD-SLAY-containing osteopontin icosamer peptide in HUVECs and in the postischemic brain. Exp Mol Med 2018; 50:e430. [PMID: 29350679 PMCID: PMC5799800 DOI: 10.1038/emm.2017.241] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2016] [Revised: 07/05/2017] [Accepted: 07/07/2017] [Indexed: 01/08/2023] Open
Abstract
Osteopontin (OPN) is a phosphorylated glycoprotein secreted into body fluids by various cell types. OPN contains arginine-glycine-aspartate (RGD) and serine-leucine-alanine-tyrosine (SLAY) motifs that bind to several integrins and mediate a wide range of cellular processes. In the present study, the proangiogenic effects of a 20-amino-acid OPN peptide (OPNpt20) containing RGD and SLAY motifs were examined in human umbilical vein endothelial cells (HUVECs) and in a rat focal cerebral ischemia model. OPNpt20 exerted robust proangiogenic effects in HUVECs by promoting proliferation, migration and tube formation. These effects were significantly reduced in OPNpt20-RAA (RGD->RAA)-treated cells, but only slightly reduced in OPNpt20-SLAA (SLAY->SLAA)-treated cells. Interestingly, a mutant peptide without both motifs failed to induce these proangiogenic processes, indicating that the RGD motif is crucial and that SLAY also has a role. In OPNpt20-treated HUVEC cultures, AKT and ERK signaling pathways were activated, but activation of these pathways and tube formation were suppressed by anti-αvβ3 antibody, indicating that OPNpt20 stimulates angiogenesis via the αvβ3-integrin/AKT and ERK pathways. The proangiogenic function of OPNpt20 was further confirmed in a rat middle cerebral artery occlusion model. Total vessel length and vessel densities were markedly greater in OPNpt20-treated ischemic brains, accompanied by induction of proangiogenic markers. Together, these results demonstrate that the 20-amino-acid OPN peptide containing RGD and SLAY motifs exerts proangiogenic effects, wherein both motifs have important roles, and these effects appear to contribute to the neuroprotective effects of this peptide in the postischemic brain.
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The role of α9β1 integrin and its ligands in the development of autoimmune diseases. J Cell Commun Signal 2017; 12:333-342. [PMID: 28975544 DOI: 10.1007/s12079-017-0413-7] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2017] [Accepted: 09/25/2017] [Indexed: 02/07/2023] Open
Abstract
Adhesion of cells to extracellular matrix proteins through integrins expressed on the cell surface is important for cell adhesion/motility, survival, and differentiation. Recently, α9β1 integrin was reported to be important for the development of autoimmune diseases including rheumatoid arthritis, multiple sclerosis, and their murine models. In addition, ligands for α9β1 integrin, such as osteopontin and tenascin-C, are well established as key regulators of autoimmune diseases. Therefore, this review focused on the role of interactions between α9β1 integrin and its ligands in the development of autoimmune diseases.
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Early and late gene expression profiles of the ovine mucosa in response to Haemonchus contortus infection employing Illumina RNA-seq technology. Parasitol Int 2017; 66:681-692. [PMID: 28552633 DOI: 10.1016/j.parint.2017.05.007] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2017] [Revised: 05/03/2017] [Accepted: 05/23/2017] [Indexed: 02/07/2023]
Abstract
We conducted herein transcriptome sequencing of the ovine abomasal tissues using the Illumina HiSeq 4000 platform to segregate early and late H. contortus-infected sheep (7 and 50days post-infected groups, respectively) from the control naive ones. A total of 548, 357 and 7 were substantially induced genes in 7days post-infection versus uninfected-control group, 50days post-infection versus 7days post-infection (7dpi), and 50days post-infection (50dpi) versus uninfected-control group, respectively. However, a total of 301, 355 and 11 were significantly repressed genes between 7dpi versus uninfected-control group, 50dpi versus 7dpi, and 50dpi versus uninfected-control group, correspondingly. This indicates that H. contortus infection induced a more potent activation of abomasal gene expression in the early stage of infection as compared to the late stage. Seven pathways were annotated by Kyoto Encyclopedia of Genes, and Genomes pathway analysis accounted for the significant percentage in early H. contortus infection. This study shows for the first time that both galectin-11 and matricellular protein osteopontin are up-regulated in abomasal tissue after chronic H. contortus infection, while galectin-4 is specifically down-regulated in the early infection. Additionally, our results showed that the induction or repression of these molecules is likely to determine the infection progression.
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Abstract
Natalizumab is a monoclonal antibody that acts as an α4 integrin antagonist to prevent leukocyte trafficking into the central nervous system. It is US Food and Drug Administration (FDA) approved for the treatment of relapsing-remitting multiple sclerosis (RRMS). Natalizumab demonstrated high efficacy in Phase III trials by reducing the annualized relapse rate, preventing multiple sclerosis (MS) lesion accumulation on magnetic resonance imaging, and decreasing the probability of sustained progression of disability. The leading safety concern with natalizumab is its association with progressive multifocal leukoencephalopathy (PML), a rare brain infection typically seen only in severely immunocompromised patients caused by reactivation of the John Cunningham virus (JCV). Careful analysis of risk factors for PML in natalizumab-treated MS patients, specifi-cally the presence of anti-JCV antibodies, has led to risk mitigation strategies to improve safety. Additional biomarkers are under investigation to further aid risk stratification. Natalizumab's high efficacy and favorable tolerability profile have led to a broad use by MS physicians, as both first-and second-line treatments. This review discusses the natalizumab efficacy, safety, and tolerability and finishes with pragmatic considerations regarding its use in clinical practice.
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Affiliation(s)
- Rachel Brandstadter
- Department of Neurology, Corinne Goldsmith Dickinson Center for Multiple Sclerosis, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Ilana Katz Sand
- Department of Neurology, Corinne Goldsmith Dickinson Center for Multiple Sclerosis, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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27
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Campagnolo P, Gormley AJ, Chow LW, Guex AG, Parmar PA, Puetzer JL, Steele JAM, Breant A, Madeddu P, Stevens MM. Pericyte Seeded Dual Peptide Scaffold with Improved Endothelialization for Vascular Graft Tissue Engineering. Adv Healthc Mater 2016; 5:3046-3055. [PMID: 27782370 DOI: 10.1002/adhm.201600699] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Revised: 09/23/2016] [Indexed: 01/22/2023]
Abstract
The development of synthetic vascular grafts for coronary artery bypass is challenged by insufficient endothelialization, which increases the risk of thrombosis, and the lack of native cellular constituents, which favors pathological remodeling. Here, a bifunctional electrospun poly(ε-caprolactone) (PCL) scaffold with potential for synthetic vascular graft applications is presented. This scaffold incorporates two tethered peptides: the osteopontin-derived peptide (Adh) on the "luminal" side and a heparin-binding peptide (Hep) on the "abluminal" side. Additionally, the "abluminal" side of the scaffold is seeded with saphenous vein-derived pericytes (SVPs) as a source of proangiogenic growth factors. The Adh peptide significantly increases endothelial cell adhesion, while the Hep peptide promotes accumulation of vascular endothelial growth factor secreted by SVPs. SVPs increase endothelial migration both in a transwell assay and a modified scratch assay performed on the PCL scaffold. Seeding of SVPs on the "abluminal"/Hep side of the scaffold further increases endothelial cell density, indicating a combinatory effect of the peptides and pericytes. Finally, SVP-seeded scaffolds are preserved by freezing in a xeno-free medium, maintaining good cell viability and function. In conclusion, this engineered scaffold combines patient-derived pericytes and spatially organized functionalities, which synergistically increase endothelial cell density and growth factor retention.
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Affiliation(s)
- Paola Campagnolo
- Department of Materials; Department of Bioengineering and Institute of Biomedical Engineering; Royal School of Mines; Imperial College London; Prince Consort Rd SW7 2AZ London UK
| | - Adam J. Gormley
- Department of Materials; Department of Bioengineering and Institute of Biomedical Engineering; Royal School of Mines; Imperial College London; Prince Consort Rd SW7 2AZ London UK
| | - Lesley W. Chow
- Department of Materials; Department of Bioengineering and Institute of Biomedical Engineering; Royal School of Mines; Imperial College London; Prince Consort Rd SW7 2AZ London UK
| | - Anne Géraldine Guex
- Department of Materials; Department of Bioengineering and Institute of Biomedical Engineering; Royal School of Mines; Imperial College London; Prince Consort Rd SW7 2AZ London UK
- National Heart and Lung Institute; Imperial College London; 435 Du Cane Road W12 0NN London UK
| | - Paresh A. Parmar
- Department of Materials; Department of Bioengineering and Institute of Biomedical Engineering; Royal School of Mines; Imperial College London; Prince Consort Rd SW7 2AZ London UK
| | - Jennifer L. Puetzer
- Department of Materials; Department of Bioengineering and Institute of Biomedical Engineering; Royal School of Mines; Imperial College London; Prince Consort Rd SW7 2AZ London UK
| | - Joseph A. M. Steele
- Department of Materials; Department of Bioengineering and Institute of Biomedical Engineering; Royal School of Mines; Imperial College London; Prince Consort Rd SW7 2AZ London UK
| | - Alexandre Breant
- Department of Materials; Department of Bioengineering and Institute of Biomedical Engineering; Royal School of Mines; Imperial College London; Prince Consort Rd SW7 2AZ London UK
| | - Paolo Madeddu
- Bristol Heart Institute; University of Bristol; Bristol Royal Infirmary; Upper Maudlin St BS2 8HW Bristol UK
| | - Molly M. Stevens
- Department of Materials; Department of Bioengineering and Institute of Biomedical Engineering; Royal School of Mines; Imperial College London; Prince Consort Rd SW7 2AZ London UK
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Abstract
Multiple sclerosis (MS) is a complex disease that causes a great deal of disability, especially in the young adult population. There have been several immunomodulatory agents that have been approved by the Food and Drug Administration for MS, including glatiramer acetate, interferon-β 1a and -β 1b, mitoxantrone, and corticosteroids. The effectiveness of these therapies has not been optimal, and drugs, such as monoclonal antibodies, that more selectively target the pathogenetic process of MS have been sought. These agents have their own intrinsic limitations such as systemic inflammatory reactions, induction of neutralizing antiantibodies, and even life-threatening infectious processes. The agent that has been in the forefront of the discussion is natalizumab, a monoclonal antibody (mAb) against α 4 integrin, which shows much promise in suppressing MS activity. However, 3 individuals treated with natalizumab developed a life-threatening infection, progressive multifocal leukoencephalopathy. This article reviews the role of mAbs in the treatment of MS, particularly their advantages over other drugs and their limitations, which have to be overcome for these agents to be at the forefront in the treatment of MS.
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Affiliation(s)
| | - Jane W. Chan
- University of Kentucky College of Medicine, Lexington,
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29
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Le Saux G, Plawinski L, Parrot C, Nlate S, Servant L, Teichmann M, Buffeteau T, Durrieu MC. Surface bound VEGF mimicking peptide maintains endothelial cell proliferation in the absence of soluble VEGF in vitro. J Biomed Mater Res A 2016; 104:1425-36. [PMID: 26845245 DOI: 10.1002/jbm.a.35677] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2015] [Revised: 12/23/2015] [Accepted: 02/02/2016] [Indexed: 01/13/2023]
Abstract
Continuous glucose monitoring is an efficient method for the management of diabetes and in limiting the complications induced by large fluctuations in glucose levels. For this, intravascular systems may assist in producing more reliable and accurate devices. However, neovascularization is a key factor to be addressed in improving their biocompatibility. In this scope, the perennial modification of the surface of an implant with the proangiogenic Vascular Endothelial Growth Factor mimic peptide (SVVYGLR peptide sequence) holds great promise. Herein, we report on the preparation of gold substrates presenting the covalently grafted SVVYGLR peptide sequence and their effect on HUVEC behavior. Effective coupling was demonstrated using XPS and PM-IRRAS. The produced surfaces were shown to be beneficial for HUVEC adhesion. Importantly, surface bound SVVYGLR is able to maintain HUVEC proliferation even in the absence of soluble VEGF. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 1425-1436, 2016.
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Affiliation(s)
| | | | - Camila Parrot
- Equipe Labellisée Contre Le Cancer, F-33607, Pessac, France
- INSERM, U869, ARNA Laboratory, Equipe Labellisée Contre Le Cancer, Bordeaux, F-33076, France
| | - Sylvain Nlate
- University of Bordeaux, CBMN, UMR 5248, Pessac, F-33600, France
| | - Laurent Servant
- University of Bordeaux, ISM, UMR 5255, Talence, F-33400, France
| | - Martin Teichmann
- Equipe Labellisée Contre Le Cancer, F-33607, Pessac, France
- INSERM, U869, ARNA Laboratory, Equipe Labellisée Contre Le Cancer, Bordeaux, F-33076, France
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30
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Jürets A, Le Bras M, Staffler G, Stein G, Leitner L, Neuhofer A, Tardelli M, Turkof E, Zeyda M, Stulnig TM. Inhibition of Cellular Adhesion by Immunological Targeting of Osteopontin Neoepitopes Generated through Matrix Metalloproteinase and Thrombin Cleavage. PLoS One 2016; 11:e0148333. [PMID: 26840958 PMCID: PMC4740464 DOI: 10.1371/journal.pone.0148333] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2015] [Accepted: 01/15/2016] [Indexed: 01/10/2023] Open
Abstract
Osteopontin (OPN), a secreted protein involved in inflammatory processes and cancer, induces cell adhesion, migration, and activation of inflammatory pathways in various cell types. Cells bind OPN via integrins at a canonical RGD region in the full length form as well as to a contiguous cryptic site that some have shown is unmasked upon thrombin or matrix metalloproteinase cleavage. Thus, the adhesive capacity of osteopontin is enhanced by proteolytic cleavage that may occur in inflammatory conditions such as obesity, atherosclerosis, rheumatoid arthritis, tumor growth and metastasis. Our aim was to inhibit cellular adhesion to recombinant truncated proteins that correspond to the N-terminal cleavage products of thrombin- or matrix metalloproteinase-cleaved OPN in vitro. We specifically targeted the cryptic integrin binding site with monoclonal antibodies and antisera induced by peptide immunization of mice. HEK 293 cells adhered markedly stronger to truncated OPN proteins than to full length OPN. Without affecting cell binding to the full length form, the raised monoclonal antibodies specifically impeded cellular adhesion to the OPN fragments. Moreover, we show that the peptides used for immunization were able to induce antisera, which impeded adhesion either to all OPN forms, including the full-length form, or selectively to the corresponding truncated recombinant proteins. In conclusion, we developed immunological tools to selectively target functional properties of protease-cleaved OPN forms, which could find applications in treatment and prevention of various inflammatory diseases and cancers.
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Affiliation(s)
- Alexander Jürets
- Christian Doppler Laboratory for Cardio-Metabolic Immunotherapy and Clinical Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | | | | | - Gesine Stein
- Christian Doppler Laboratory for Cardio-Metabolic Immunotherapy and Clinical Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Lukas Leitner
- Christian Doppler Laboratory for Cardio-Metabolic Immunotherapy and Clinical Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Angelika Neuhofer
- Christian Doppler Laboratory for Cardio-Metabolic Immunotherapy and Clinical Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Matteo Tardelli
- Christian Doppler Laboratory for Cardio-Metabolic Immunotherapy and Clinical Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Edvin Turkof
- Department of Plastic and Reconstructive Surgery, Medical University of Vienna, Vienna, Austria
| | - Maximilian Zeyda
- Christian Doppler Laboratory for Cardio-Metabolic Immunotherapy and Clinical Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Thomas M. Stulnig
- Christian Doppler Laboratory for Cardio-Metabolic Immunotherapy and Clinical Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- * E-mail:
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31
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Inoue M, Shinohara ML. Cutting edge: Role of osteopontin and integrin αv in T cell-mediated anti-inflammatory responses in endotoxemia. THE JOURNAL OF IMMUNOLOGY 2015; 194:5595-8. [PMID: 25972484 DOI: 10.4049/jimmunol.1500623] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/18/2015] [Accepted: 04/25/2015] [Indexed: 01/05/2023]
Abstract
The immune system is equipped with mechanisms that downregulate hyperinflammation to avoid collateral damage. We demonstrated recently that unprimed T cells downregulate macrophage TNF production through direct interaction with macrophages in the spleen during LPS endotoxemia. How T cell migration toward macrophages occurs upon LPS injection is still not clear. In this study, we demonstrate that secreted osteopontin (sOPN) plays a role in the T cell migration to initiate the suppression of hyperinflammation during endotoxemia. Osteopontin levels in splenic macrophages were upregulated 2 h after LPS treatment, whereas T cell migration toward macrophages was observed 3 h after treatment. Neutralization of sOPN and blockade of its receptor, integrin αv, significantly inhibited CD4(+) T cell migration and increased susceptibility to endotoxemia. Our study demonstrates that the sOPN/integrin αv axis, which induces T cell chemotaxis toward macrophages, is critical for suppressing hyperinflammation during the first 3 h of endotoxemia.
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Affiliation(s)
- Makoto Inoue
- Department of Immunology, Duke University School of Medicine, Durham, NC 27710; and
| | - Mari L Shinohara
- Department of Immunology, Duke University School of Medicine, Durham, NC 27710; and Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710
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32
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Hutcheson R, Terry R, Hutcheson B, Jadhav R, Chaplin J, Smith E, Barrington R, Proctor SD, Rocic P. miR-21-mediated decreased neutrophil apoptosis is a determinant of impaired coronary collateral growth in metabolic syndrome. Am J Physiol Heart Circ Physiol 2015; 308:H1323-35. [PMID: 25840830 DOI: 10.1152/ajpheart.00654.2014] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2014] [Accepted: 03/21/2015] [Indexed: 11/22/2022]
Abstract
Coronary collateral growth (CCG) is impaired in metabolic syndrome. microRNA-21 (miR-21) is a proproliferative and antiapoptotic miR, which we showed to be elevated in metabolic syndrome. Here we investigate whether impaired CCG in metabolic syndrome involved miR-21-mediated aberrant apoptosis. Normal Sprague-Dawley (SD) and metabolic syndrome [J. C. Russel (JCR)] rats underwent transient, repetitive coronary artery occlusion [repetitive ischemia (RI)]. Antiapoptotic Bcl-2, phospho-Bad, and Bcl-2/Bax dimers were increased on days 6 and 9 RI, and proapoptotic Bax and Bax/Bax dimers and cytochrome-c release concurrently decreased in JCR versus SD rats. Active caspases were decreased in JCR versus SD rats (~50%). Neutrophils increased transiently on day 3 RI in the collateral-dependent zone of SD rats but remained elevated in JCR rats, paralleling miR-21 expression. miR-21 downregulation by anti-miR-21 induced neutrophil apoptosis and decreased Bcl-2 and Bcl-2/Bax dimers (~75%) while increasing Bax/Bax dimers, cytochrome-c release, and caspase activation (~70, 400, and 400%). Anti-miR-21 also improved CCG in JCR rats (~60%). Preventing neutrophil infiltration with blocking antibodies resulted in equivalent CCG recovery, confirming a major role for deregulated neutrophil apoptosis in CCG impairment. Neutrophil and miR-21-dependent CCG inhibition was in significant part mediated by increased oxidative stress. We conclude that neutrophil apoptosis is integral to normal CCG and that inappropriate prolonged miR-21-mediated survival of neutrophils plays a major role in impaired CCG, in part via oxidative stress generation.
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Affiliation(s)
- Rebecca Hutcheson
- Department of Pharmacology, New York Medical College, Valhalla, New York
| | - Russell Terry
- Department of Biochemistry and Molecular Biology, University of South Alabama College of Medicine, Mobile, Alabama
| | - Brenda Hutcheson
- Department of Pharmacology, New York Medical College, Valhalla, New York
| | - Rashmi Jadhav
- Department of Biochemistry and Molecular Biology, University of South Alabama College of Medicine, Mobile, Alabama
| | - Jennifer Chaplin
- Department of Biochemistry and Molecular Biology, University of South Alabama College of Medicine, Mobile, Alabama
| | - Erika Smith
- Department of Biochemistry and Molecular Biology, University of South Alabama College of Medicine, Mobile, Alabama
| | - Robert Barrington
- Department of Microbiology and Immunology, University of South Alabama College of Medicine, Mobile, Alabama; and
| | - Spencer D Proctor
- Metabolic and Cardiovascular Diseases Laboratory, Alberta Institute for Human Nutrition, University of Alberta, Edmonton, Alberta, Canada
| | - Petra Rocic
- Department of Pharmacology, New York Medical College, Valhalla, New York;
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Kläning E, Christensen B, Bajic G, Hoffmann SV, Jones NC, Callesen MM, Andersen GR, Sørensen ES, Vorup-Jensen T. Multiple low-affinity interactions support binding of human osteopontin to integrin αXβ2. BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS 2015; 1854:930-8. [PMID: 25839998 DOI: 10.1016/j.bbapap.2015.03.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/07/2015] [Revised: 03/18/2015] [Accepted: 03/22/2015] [Indexed: 01/11/2023]
Abstract
Integrin α(X)β(2) (also known as complement receptor 4, p150,95, or CD11c/CD18) is expressed in the cell membrane of myeloid leukocytes. α(X)β(2) has been reported to bind a large number of structurally unrelated ligands, often with a shared molecular character in the presence of polyanionic stretches in poorly folded proteins or glucosaminoglycans. Nevertheless, it is unclear what chemical sources of polyanionicity enable the binding by α(X)β(2). Osteopontin (OPN) is an intrinsically disordered protein, which facilitates phagocytosis via the integrin α(X)β(2). Unlike for other integrins, neither the RGD nor the SVVYGLR motifs account for this binding, and the molecular basis of OPN binding by α(X)β(2) remains uncharacterized. Here, we show that the monovalent interactions between the ligand-binding domain of α(X)β(2) and OPN, its fragments, or caseins are weak, with dissociation constants higher than 10(-5)M but with high apparent stoichiometries. From comparison with cell adhesion studies, the discrimination between α(X)β(2) ligands and non-ligands appears to rely on these apparent stoichiometries in a way, which involves glutamate rather than aspartate side chains. Surprisingly, the extensive, negatively charged phosphorylation of OPN is not contributing to α(X)β(2) binding. Furthermore, synchrotron radiation circular spectroscopy excludes that the phosphorylation affects the general folding of OPN. Taken together, our quantitative analyses reveal a mode of ligand recognition by integrin α(X)β(2), which seem to differ in principles considerably from other OPN receptors.
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Affiliation(s)
- Eva Kläning
- Dept. of Molecular Biology and Genetics Aarhus University, Aarhus, Denmark; Dept. of Biomedicine, Denmark
| | - Brian Christensen
- Dept. of Molecular Biology and Genetics Aarhus University, Aarhus, Denmark
| | - Goran Bajic
- Dept. of Molecular Biology and Genetics Aarhus University, Aarhus, Denmark
| | - Søren V Hoffmann
- Institute for Storage Ring Facilities Aarhus (ISA), Dept. of Physics and Astronomy & Center for Storage Ring Facilities Aarhus, Denmark
| | - Nykola C Jones
- Institute for Storage Ring Facilities Aarhus (ISA), Dept. of Physics and Astronomy & Center for Storage Ring Facilities Aarhus, Denmark
| | - Morten M Callesen
- Dept. of Molecular Biology and Genetics Aarhus University, Aarhus, Denmark
| | - Gregers R Andersen
- Dept. of Molecular Biology and Genetics Aarhus University, Aarhus, Denmark
| | - Esben S Sørensen
- Dept. of Molecular Biology and Genetics Aarhus University, Aarhus, Denmark; Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Aarhus Denmark
| | - Thomas Vorup-Jensen
- Dept. of Biomedicine, Denmark; Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Aarhus Denmark; MEMBRANES Research Center, Aarhus University, Aarhus, Denmark.
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A novel cryptic binding motif, LRSKSRSFQVSDEQY, in the C-terminal fragment of MMP-3/7-cleaved osteopontin as a novel ligand for α9β1 integrin is involved in the anti-type II collagen antibody-induced arthritis. PLoS One 2014; 9:e116210. [PMID: 25545242 PMCID: PMC4278882 DOI: 10.1371/journal.pone.0116210] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2014] [Accepted: 12/06/2014] [Indexed: 12/04/2022] Open
Abstract
Osteopontin (OPN) is a multifunctional protein that has been linked to various intractable inflammatory diseases. One way by which OPN induces inflammation is the production of various functional fragments by enzyme cleavage. It has been well appreciated that OPN is cleaved by thrombin, and/or matrix metalloproteinase-3 and -7 (MMP-3/7). Although the function of thrombin-cleaved OPN is well characterized, little is known about the function of MMP-3/7-cleaved OPN. In this study, we found a novel motif, LRSKSRSFQVSDEQY, in the C-terminal fragment of MMP-3/7-cleaved mouse OPN binds to α9β1 integrin. Importantly, this novel motif is involved in the development of anti-type II collagen antibody-induced arthritis (CAIA). This study provides the first in vitro and in vivo evidence that OPN cleavage by MMP-3/7 is an important regulatory mechanism for CAIA.
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35
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Osteopontin binding to the alpha 4 integrin requires highest affinity integrin conformation, but is independent of post-translational modifications of osteopontin. Matrix Biol 2014; 41:19-25. [PMID: 25446551 DOI: 10.1016/j.matbio.2014.11.005] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2014] [Revised: 11/20/2014] [Accepted: 11/22/2014] [Indexed: 12/17/2022]
Abstract
Osteopontin (OPN) is a ligand for the α4ß1 integrin, but the physiological importance of this binding is not well understood. Here, we have assessed the effect of post-translational modifications on OPN binding to the α4 integrin on cultured human leukocyte cell lines and compared OPN interaction with α4 integrin to that of VCAM and fibronectin. Jurkat cells, whose α4 integrins are inherently activated, adhered to different preparations of OPN in the presence of Mn(2+): the EC50 of adhesion was not affected by phosphorylation or glycosylation status. Thrombin cleavage of OPN at the C-terminus of the α4 integrin-binding site also did not affect binding affinity. THP-1 cells express a low-affinity conformation of the integrin and adhered to OPN only in the presence of Mn(2+) plus PMA or an activating antibody. This was in contrast to VCAM and fibronectin: THP-1 cells adhered to these ligands without integrin activation. Studies with ligand-induced binding site antibodies demonstrated that the SVVYGLR peptide of OPN bound to the α4 integrin with a similar affinity as the LDV peptide of fibronectin, suggesting that a high off-rate is responsible for the reduced binding of OPN to the low-affinity forms of this integrin. Together, the results suggest OPN has very low affinity for the α4 integrin on human leukocytes under physiological conditions.
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36
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Almonte-Becerril M, Costell M, Kouri JB. Changes in the integrins expression are related with the osteoarthritis severity in an experimental animal model in rats. J Orthop Res 2014; 32:1161-6. [PMID: 24839051 DOI: 10.1002/jor.22649] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2013] [Accepted: 04/24/2014] [Indexed: 02/04/2023]
Abstract
We identify changes in the expression and localization of α5, α4, and α2 integrins during osteoarthritis (OA) pathogenesis in a rat experimental model. The changes were concomitant with variations in the extracellular matrix (ECM) content and the increase of metalloproteinases (MMPs) activity during OA pathogenesis, which were analyzed by immunofluorescence and Western blot assays. Our results showed an increased expression of α5 and α2 integrins at OA late stages, which was co-related with changes in the ECM content, as a consequence of the MMPs activity. In addition, this is the first report that has shown the presence of α4 integrin since OA early stages, which was co-related with the loss of proteoglycans and clusters formation. However, at late OA stages, the increased expression of α4 integrin in the middle and deep zones of the cartilage was also co-related with the abnormal endochondral ossification of the cartilage through its interaction with osteopontin. Finally, we conclude that ECM-chondrocytes interaction through specific cell receptors is essential to maintain the cartilage homeostasis. However, due to integrins cell signaling is ligand-dependent; changes in the ECM contents could induce activation of either anabolic or catabolic processes, which limits the reparative capacity of chondrocytes, favoring OA severity.
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Affiliation(s)
- Maylin Almonte-Becerril
- Departamento de Infectómica y Patogénesis Molecular, Centro de investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), México, DF, México
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Zhang F, Luo W, Li Y, Gao S, Lei G. Role of osteopontin in rheumatoid arthritis. Rheumatol Int 2014; 35:589-95. [PMID: 25163663 DOI: 10.1007/s00296-014-3122-z] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2014] [Accepted: 08/22/2014] [Indexed: 01/01/2023]
Abstract
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by joint swelling, joint tenderness, and destruction of synovial joints, leading to severe disability and premature mortality. RA is a multifactorial disease with genetic, environmental, and stochastic components related to its susceptibility. It has been demonstrated that the expression of osteopontin (OPN) is upregulated in the RA patients. Numerous studies have indicated that the full-length OPN or even OPN fragments, such as thrombin-cleaved OPN and its receptors, play the key roles in RA pathogenesis. Therapeutic application of siRNA to target OPN or neutralizing antibodies related to OPN epitopes in RA animal models are in progress, and some results are encouraging. However, there is a long way to go along with the clinical trials. This review focuses on the recent development in research associated with the OPN role in the pathogenesis of RA and provides insights concerning the OPN targeting as therapeutic approaches for patients with RA.
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Affiliation(s)
- Fangjie Zhang
- Department of Orthopaedics, Xiangya Hospital, Central South University, No. 87 Xiangya Road, Changsha, 410008, Hunan, China
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Murphy-Ullrich JE, Sage EH. Revisiting the matricellular concept. Matrix Biol 2014; 37:1-14. [PMID: 25064829 PMCID: PMC4379989 DOI: 10.1016/j.matbio.2014.07.005] [Citation(s) in RCA: 299] [Impact Index Per Article: 27.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2014] [Revised: 07/07/2014] [Accepted: 07/08/2014] [Indexed: 12/16/2022]
Abstract
The concept of a matricellular protein was first proposed by Paul Bornstein in the mid-1990s to account for the non-lethal phenotypes of mice with inactivated genes encoding thrombospondin-1, tenascin-C, or SPARC. It was also recognized that these extracellular matrix proteins were primarily counter or de-adhesive. This review reappraises the matricellular concept after nearly two decades of continuous investigation. The expanded matricellular family as well as the diverse and often unexpected functions, cellular location, and interacting partners/receptors of matricellular proteins are considered. Development of therapeutic strategies that target matricellular proteins are discussed in the context of pathology and regenerative medicine.
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Affiliation(s)
- Joanne E Murphy-Ullrich
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294-0019, United States.
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Chagan-Yasutan H, Lacuesta TL, Ndhlovu LC, Oguma S, Leano PSA, Telan EFO, Kubo T, Morita K, Uede T, Dimaano EM, Hattori T. Elevated levels of full-length and thrombin-cleaved osteopontin during acute dengue virus infection are associated with coagulation abnormalities. Thromb Res 2014; 134:449-54. [PMID: 24861695 DOI: 10.1016/j.thromres.2014.05.003] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2014] [Revised: 05/04/2014] [Accepted: 05/05/2014] [Indexed: 01/10/2023]
Abstract
INTRODUCTION Dengue virus (DENV) is transmitted by the mosquito vector, and causes a wide range of symptoms that lead to dengue fever (DF) or life-threatening dengue hemorrhagic fever (DHF). The host and viral correlates that contribute to DF and DHF are complex and poorly understood, but appear to be linked to inflammation and impaired coagulation. Full-length osteopontin (FL-OPN), a glycoprotein, and its activated thrombin-cleaved product, trOPN, integrate multiple immunological signals through the induction of pro-inflammatory cytokines. MATERIALS AND METHOD To understand the role of OPN in DENV-infection, we assessed circulating levels of FL-OPN, trOPN, and several coagulation markers (D-dimer, thrombin-antithrombin complex [TAT], thrombomodulin [TM], and ferritin in blood obtained from 65 DENV infected patients in the critical and recovery phases of DF and DHF during a dengue virus epidemic in the Philippines in 2010. RESULTS Levels of FL-OPN, trOPN, D-dimer, TAT, and TM were significantly elevated in the critical phase in both the DF and DHF groups, as compared with healthy controls. During the recovery phase, FL-OPN levels declined while trOPN levels increased dramatically in both the DF and DHF groups. FL-OPN levels were directly correlated with D-dimer and ferritin levels, while the generation of trOPN was associated with TAT levels, platelet counts, and viral RNA load. CONCLUSION Our study demonstrated the marked elevation of plasma levels of FL-OPN and thrombin-cleaved OPN product, trOPN, in DENV-infection for the first time. Further studies on the biological functions of these matricellular proteins in DENV-infection would clarify its pathogenesis.
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Affiliation(s)
- Haorile Chagan-Yasutan
- Division of Emerging Infectious Diseases, Department of Internal Medicine, Graduate School of Medicine; Laboratory of Disaster-related Infectious Disease, International Research Institute of Disaster Science, Tohoku University, Sendai, Japan
| | | | - Lishomwa C Ndhlovu
- Department of Tropical Medicine, John A. Burns School of Medicine, University of HI, Manoa, USA
| | - Shigeru Oguma
- Medical Informatics Division, Takeda General Hospital, Kyoto, Japan
| | - Prisca Susan A Leano
- National Reference Laboratory for HIV/AIDS, Hepatitis, and other STDs, STD/AIDS Cooperative Central Laboratory, Manila, Philippines
| | - Elizabeth Freda O Telan
- National Reference Laboratory for HIV/AIDS, Hepatitis, and other STDs, STD/AIDS Cooperative Central Laboratory, Manila, Philippines
| | - Toru Kubo
- Department of Virology, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan
| | - Kouichi Morita
- Department of Virology, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan
| | - Toshimitsu Uede
- Division of Molecular Immunology, Institute for Genetic Medicine, Hokkaido University, Japan
| | - Efren M Dimaano
- Department of Blood Borne Diseases, San Lazaro Hospital, Manila, Philippines
| | - Toshio Hattori
- Division of Emerging Infectious Diseases, Department of Internal Medicine, Graduate School of Medicine; Laboratory of Disaster-related Infectious Disease, International Research Institute of Disaster Science, Tohoku University, Sendai, Japan.
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Nagoshi S. Osteopontin: Versatile modulator of liver diseases. Hepatol Res 2014; 44:22-30. [PMID: 23701387 DOI: 10.1111/hepr.12166] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2013] [Revised: 05/12/2013] [Accepted: 05/16/2013] [Indexed: 12/16/2022]
Abstract
Osteopontin (OPN) is a multifunctional protein, involved in pathological conditions including inflammation, immunity, angiogenesis, fibrosis and cancer progression in various tissues. Hepatic inflammation and fibrosis induced by feeding with a diet deficient in methionine and choline (MCD diet) were markedly attenuated in OPN knockout mice when compared with wild-type mice in the model of non-alcoholic steatohepatitis (NASH). Hepatic cholangiocytes, myofibroblastic stellate cells and natural killer T cells were suggested to secret OPN in mice fed an MCD diet. Plasma and hepatic OPN levels were significantly higher in patients with NASH with advanced fibrosis than in those with early fibrosis. Hepatic OPN mRNA level was correlated with hepatic neutrophil infiltration and fibrosis in patients with alcoholic liver diseases. In those with hepatocellular carcinoma (HCC), OPN levels in plasma and HCC were prognostic factors after liver resection or transplantation. Downregulation of OPN inhibited tumor growth and lung metastasis in nude mice implanted with HCC cells. The single nucleotide polymorphism in the promoter region of the OPN gene was shown to be associated with activity of hepatitis in chronic hepatitis C patients, prognosis in patients with HCC, and growth and lung metastasis of HCC xenografts in nude mice. OPN was reported to be a downstream effecter of Hedgehog pathway, which modulates hepatic fibrosis and carcinogenesis. This review focuses on the roles of OPN in hepatic inflammation, fibrosis and cancer progression. Further elucidation of cellular interactions and molecular mechanisms associated with OPN actions may contribute to development of novel strategies for treatment of the liver diseases.
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Affiliation(s)
- Sumiko Nagoshi
- Department of Gastroenterology and Hepatology, Saitama Medical Center, Saitama Medical University, Saitama, Japan
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Zhang MX, Xu YJ, Zhu MC, Yan F. Overexpressed Ostepontin-c as a Potential Biomarker for Esophageal Squamous Cell Carcinoma. Asian Pac J Cancer Prev 2013; 14:7315-9. [DOI: 10.7314/apjcp.2013.14.12.7315] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
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Peptide-grafted poly(ethylene glycol) hydrogels support dynamic adhesion of endothelial progenitor cells. Acta Biomater 2013; 9:8279-89. [PMID: 23770139 DOI: 10.1016/j.actbio.2013.05.023] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2013] [Revised: 05/16/2013] [Accepted: 05/21/2013] [Indexed: 12/20/2022]
Abstract
This study investigated the dynamic adhesion of endothelial progenitor cells (EPCs) to peptide-grafted poly(ethylene glycol) diacrylate (PEGDA) hydrogels and determined the relative ability of RGDS, REDV and YIGSRG peptides to reduce the velocity of EPC rolling. Circulating EPCs are key mediators of endothelium repair and have been shown to accelerate re-endothelialization, which is important in reducing the incidence of restenosis following stent placement and occlusion of small diameter vascular grafts. However, to exploit these capabilities for tissue engineering applications, more knowledge is needed about EPC binding to the vascular wall under shear and, in particular, whether the incorporation of peptide ligands into biomaterials can support the process of EPC rolling or maintain EPC adhesion. This study specifically examined one type of EPCs endothelial colony forming cells (ECFCs), based on their ability to be expanded in culture and differentiate into mature endothelial cells. The amount of grafted PEG-peptide was shown to be dependent on the concentration of PEG-peptide grafting solution photopolymerized onto the hydrogel surface. The ECFC strength of adhesion on PEG-RDGS grafted hydrogels exceeded 350 dyn cm(-2) for 85% of adherent cells. PEG-RGDS grafted hydrogels supported ECFC rolling, whereas ECFC velocity on the negative control PEG-RGES grafted hydrogels and on the "blank slate" PEGDA hydrogels was substantially higher than the cutoff velocity for cell rolling. The ECFC rolling velocity on PEG-RDGS grafted hydrogels depended on the shear rate; as shear rate was increased from 20 s(-1) to 120 s(-1), ECFC rolling velocity increased from 103±3 μm s(-1) to 741±28 μm s(-1). REDV and YIGSRG, which are known to preferentially support endothelial cell adhesion, also supported ECFC rolling. Interestingly, the rolling velocity of ECFCs on PEG-REDV grafted hydrogels was significantly lower than on PEG-YIGSRG or on PEG-RGDS grafted hydrogels. Understanding the dynamic adhesion of ECFCs to peptide-grafted hydrogels is the first step towards understanding the similarities and differences of EPCs from mature endothelial cells and improving the ability to sequester EPCs to biomaterial surfaces in order to promote intravascular re-endothelialization.
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Chua GL, Patra AT, Tan SM, Bhattacharjya S. NMR structure of integrin α4 cytosolic tail and its interactions with paxillin. PLoS One 2013; 8:e55184. [PMID: 23383101 PMCID: PMC3561355 DOI: 10.1371/journal.pone.0055184] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2012] [Accepted: 12/19/2012] [Indexed: 12/24/2022] Open
Abstract
Background Integrins are a group of transmembrane signaling proteins that are important in biological processes such as cell adhesion, proliferation and migration. Integrins are α/β hetero-dimers and there are 24 different integrins formed by specific combinations of 18 α and 8 β subunits in humans. Generally, each of these subunits has a large extracellular domain, a single pass transmembrane segment and a cytosolic tail (CT). CTs of integrins are important in bidirectional signal transduction and they associate with a large number of intracellular proteins. Principal Findings Using NMR spectroscopy, we determined the 3-D structure of the full-length α4 CT (Lys968-Asp999) and characterize its interactions with the adaptor protein paxillin. The α4 CT assumes an overall helical structure with a kink in its membrane proximal region. Residues Gln981-Asn997 formed a continuous helical conformation that may be sustained by potential ionic and/or hydrogen bond interactions and packing of aromatic-aliphatic side-chains. 15N-1H HSQC NMR experiments reveal interactions of the α4 CT C-terminal region with a fragment of paxillin (residues G139-K277) that encompassed LD2-LD4 repeats. Residues of these LD repeats including their adjoining linkers showed α4 CT binding-induced chemical shift changes. Furthermore, NMR studies using LD-containing peptides showed predominant interactions between LD3 and LD4 of paxillin and α4 CT. Docked structures of the α4 CT with these LD repeats suggest possible polar and/or salt-bridge and non-polar packing interactions. Significance The current study provides molecular insights into the structural diversity of α CTs of integrins and interactions of integrin α4 CT with the adaptor protein paxillin.
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Affiliation(s)
- Geok-Lin Chua
- School of Biological Sciences, Nanyang Technological University, Singapore, Singapore
| | - Alok Tanala Patra
- School of Biological Sciences, Nanyang Technological University, Singapore, Singapore
| | - Suet-Mien Tan
- School of Biological Sciences, Nanyang Technological University, Singapore, Singapore
- * E-mail: (SB); (SMT)
| | - Surajit Bhattacharjya
- School of Biological Sciences, Nanyang Technological University, Singapore, Singapore
- * E-mail: (SB); (SMT)
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Yamaguchi Y, Shao Z, Sharif S, Du XY, Myles T, Merchant M, Harsh G, Glantz M, Recht L, Morser J, Leung LLK. Thrombin-cleaved fragments of osteopontin are overexpressed in malignant glial tumors and provide a molecular niche with survival advantage. J Biol Chem 2012. [PMID: 23204518 DOI: 10.1074/jbc.m112.362954] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Osteopontin (OPN), which is highly expressed in malignant glioblastoma (GBM), possesses inflammatory activity modulated by proteolytic cleavage by thrombin and plasma carboxypeptidase B2 (CPB2) at a highly conserved cleavage site. Full-length OPN (OPN-FL) was elevated in cerebrospinal fluid (CSF) samples from all cancer patients compared with noncancer patients. However, thrombin-cleaved OPN (OPN-R) and thrombin/CPB2-double-cleaved OPN (OPN-L) levels were markedly increased in GBM and non-GBM gliomas compared with systemic cancer and noncancer patients. Cleaved OPN constituted ∼23 and ∼31% of the total OPN in the GBM and non-GBM CSF samples, respectively. OPN-R was also elevated in GBM tissues. Thrombin-antithrombin levels were highly correlated with cleaved OPN, but not OPN-FL, suggesting that the cleaved OPN fragments resulted from increased thrombin and CPB2 in this extracellular compartment. Levels of VEGF and CCL4 were increased in CSF of GBM and correlated with the levels of cleaved OPN. GBM cell lines were more adherent to OPN-R and OPN-L than OPN-FL. Adhesion to OPN altered gene expression, in particular genes involved with cellular processes, cell cycle regulation, death, and inflammation. OPN and its cleaved forms promoted motility of U-87 MG cells and conferred resistance to apoptosis. Although functional mutation of the RGD motif in OPN largely abolished these functions, OPN(RAA)-R regained significant cell binding and signaling function, suggesting that the SVVYGLR motif in OPN-R may substitute for the RGD motif if the latter becomes inaccessible. OPN cleavage contributes to GBM development by allowing more cells to bind in niches where they acquire anti-apoptotic properties.
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Affiliation(s)
- Yasuto Yamaguchi
- Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, USA
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Lei Y, Rémy M, Labrugère C, Durrieu MC. Peptide immobilization on polyethylene terephthalate surfaces to study specific endothelial cell adhesion, spreading and migration. JOURNAL OF MATERIALS SCIENCE. MATERIALS IN MEDICINE 2012; 23:2761-2772. [PMID: 22878726 DOI: 10.1007/s10856-012-4736-x] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/29/2012] [Accepted: 07/26/2012] [Indexed: 06/01/2023]
Abstract
To control specific endothelial cell (EC) functions, cell adhesive RGDS, EC specific REDV and YIGSR peptides, and angiogenic SVVYGLR sequences were covalently immobilized onto polyethylene terephthalate (PET) surfaces for the purpose of cell culture. X-ray photoelectron spectroscopy, atomic force microscopy, fluorescence microscopy and contact angle measurement were employed for characterization of surface modifications. The peptide density on PET surfaces was evaluated by fluorescence microscopy. The surfaces immobilized with peptides were exposed to human umbilical vein endothelial cells to study their specific effects onto EC functions. The results showed that the surface functionalized by these peptides enhanced the EC adhesion, spreading and migration as compared with native PET surfaces. Specifically, the RGDS peptides induced more cell adhesion than other peptides. The YIGSR and SVVYGLR sequences induced more cell spreading and cell migration, represented by intense focal adhesion at the leading edges of cell spreading and migration. The bi-functionalization of RGDS and SVVYGLR peptides (MIX) combined the advantages of both peptides and induced significant EC adhesion, spreading and migration. Our study indicates that the surface functionalization by peptides specific for ECs, especially the combination of RGDS with SVVYGLR or YIGSR peptides, has potential applications in promoting endothelialization of vascular prostheses and for construction of vascularized tissues in tissue engineering.
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Affiliation(s)
- Yifeng Lei
- Université Bordeaux Segalen, Inserm U1026, Bioingénierie Tissulaire, Bordeaux, France.
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Park KM, Lee Y, Son JY, Bae JW, Park KD. In Situ SVVYGLR Peptide Conjugation into Injectable Gelatin-Poly(ethylene glycol)-Tyramine Hydrogel via Enzyme-Mediated Reaction for Enhancement of Endothelial Cell Activity and Neo-Vascularization. Bioconjug Chem 2012; 23:2042-50. [DOI: 10.1021/bc300110b] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Affiliation(s)
- Kyung Min Park
- Department of Molecular Science and
Technology, Ajou University, Suwon, 443-749
Republic of Korea
| | - Yunki Lee
- Department of Molecular Science and
Technology, Ajou University, Suwon, 443-749
Republic of Korea
| | - Joo Young Son
- Department of Molecular Science and
Technology, Ajou University, Suwon, 443-749
Republic of Korea
| | - Jin Woo Bae
- Department of Molecular Science and
Technology, Ajou University, Suwon, 443-749
Republic of Korea
| | - Ki Dong Park
- Department of Molecular Science and
Technology, Ajou University, Suwon, 443-749
Republic of Korea
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Lei Y, Zouani OF, Rémy M, Ayela C, Durrieu MC. Geometrical microfeature cues for directing tubulogenesis of endothelial cells. PLoS One 2012; 7:e41163. [PMID: 22829923 PMCID: PMC3400641 DOI: 10.1371/journal.pone.0041163] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2012] [Accepted: 06/18/2012] [Indexed: 12/21/2022] Open
Abstract
Angiogenesis, the formation of new blood vessels by sprouting from pre-existing ones, is critical for the establishment and maintenance of complex tissues. Angiogenesis is usually triggered by soluble growth factors such as VEGF. However, geometrical cues also play an important role in this process. Here we report the induction of angiogenesis solely by SVVYGLR peptide micropatterning on polymer surfaces. SVVYGLR peptide stripes were micropatterned onto polymer surfaces by photolithography to study their effects on endothelial cell (EC) behavior. Our results showed that the EC behaviors (cell spreading, orientation and migration) were significantly more guided and regulated on narrower SVVYGLR micropatterns (10 and 50 µm) than on larger stripes (100 µm). Also, EC morphogenesis into tube formation was switched on onto the smaller patterns. We illustrated that the central lumen of tubular structures can be formed by only one-to-four cells due to geometrical constraints on the micropatterns which mediated cell-substrate adhesion and generated a correct maturation of adherens junctions. In addition, sprouting of ECs and vascular networks were also induced by geometrical cues on surfaces micropatterned with SVVYGLR peptides. These micropatterned surfaces provide opportunities for mimicking angiogenesis by peptide modification instead of exogenous growth factors. The organization of ECs into tubular structures and the induction of sprouting angiogenesis are important towards the fabrication of vascularized tissues, and this work has great potential applications in tissue engineering and tissue regeneration.
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Affiliation(s)
- Yifeng Lei
- INSERM U1026, Université Victor Segalen Bordeaux 2, Bordeaux, France
- CBMN, UMR CNRS 5248, Université Bordeaux 1, Pessac, France
- * E-mail: (YL); (OFZ)
| | - Omar F. Zouani
- INSERM U1026, Université Victor Segalen Bordeaux 2, Bordeaux, France
- CBMN, UMR CNRS 5248, Université Bordeaux 1, Pessac, France
- * E-mail: (YL); (OFZ)
| | - Murielle Rémy
- INSERM U1026, Université Victor Segalen Bordeaux 2, Bordeaux, France
| | - Cédric Ayela
- IMS, UMR CNRS 5218, Université de Bordeaux, Talence, France
| | - Marie-Christine Durrieu
- INSERM U1026, Université Victor Segalen Bordeaux 2, Bordeaux, France
- CBMN, UMR CNRS 5248, Université Bordeaux 1, Pessac, France
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Modulation of integrin α4β1 by ADAM28 promotes lymphocyte adhesion and transendothelial migration. Cell Biol Int 2012; 35:1043-53. [PMID: 21332445 DOI: 10.1042/cbi20100885] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
ADAMs (a disintegrin and metalloproteinase) are a family of type I transmembrane glycoproteins related to snake venom metalloproteases and disintegrins. They are regulatory proteins that modulate intercellular adhesion and the bioavailability of growth factors, and have been implicated in many disease states, including cancer, immunity and inflammation. One member of the ADAM family, ADAM28, has been reported to bind to the integrin α4β1 in humans; however, the distribution of ADAM28 and the biological consequences of ADAM28-α4β1 interactions are yet to be fully elucidated. The expression of ADAM28 in human and murine tissues was examined by multiple Affymetrix microarray analyses, real-time RT-PCR (reverse transcription-PCR) and immunohistochemical staining. We found that ADAM28 has a relatively restricted expression pattern in mouse and human and is highly expressed in the B-lymphocyte lineage, including chronic lymphocytic leukaemic B-cells. The murine B-lymphoma line L1-2 and recombinant soluble murine ADAM28 were used to investigate ADAM28-α4β1 interactions. Our data reveal that ADAM28 binding to α4β1 is typical of integrin-ligand interactions, since it is attenuated by anti-functional integrin antibodies, and is enhanced by Mn2+ and the integrin mAb (monoclonal antibody) 9EG7. However, a key finding was that soluble ADAM28 unexpectedly enhanced α4β1-dependent cell adhesion to VCAM-1 (vascular cell adhesion molecule-1). In so doing ADAM28 was able to influence lymphocyte adhesion to, and migration through, endothelial monolayers, suggesting a physiological role for ADAM28 in regulating the specific spatial and temporal transendothelial migration of lymphocytes.
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Arjomandi M, Frelinger J, Donde A, Wong H, Yellamilli A, Raymond W. Secreted osteopontin is highly polymerized in human airways and fragmented in asthmatic airway secretions. PLoS One 2011; 6:e25678. [PMID: 22031818 PMCID: PMC3198733 DOI: 10.1371/journal.pone.0025678] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2011] [Accepted: 09/09/2011] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Osteopontin (OPN) is a member of the small integrin-binding ligand N-linked glycoprotein (SIBLING) family and a cytokine with diverse biologic roles. OPN undergoes extensive post-translational modifications, including polymerization and proteolytic fragmentation, which alters its biologic activity. Recent studies suggest that OPN may contribute to the pathogenesis of asthma. METHODOLOGY To determine whether secreted OPN (sOPN) is polymerized in human airways and whether it is qualitatively different in asthma, we used immunoblotting to examine sOPN in bronchoalveolar lavage (BAL) fluid samples from 12 healthy and 21 asthmatic subjects (and in sputum samples from 27 healthy and 21 asthmatic subjects). All asthmatic subjects had mild to moderate asthma and abstained from corticosteroids during the study. Furthermore, we examined the relationship between airway sOPN and cellular inflammation. PRINCIPAL FINDINGS We found that sOPN in BAL fluid and sputum exists in polymeric, monomeric, and cleaved forms, with most of it in polymeric form. Compared to healthy subjects, asthmatic subjects had proportionately less polymeric sOPN and more monomeric and cleaved sOPN. Polymeric sOPN in BAL fluid was associated with increased alveolar macrophage counts in airways in all subjects. CONCLUSIONS These results suggest that sOPN in human airways (1) undergoes extensive post-translational modification by polymerization and proteolytic fragmentation, (2) is more fragmented and less polymerized in subjects with mild to moderate asthma, and (3) may contribute to recruitment or survival of alveolar macrophages.
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Affiliation(s)
- Mehrdad Arjomandi
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.
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Abstract
Osteopontin (OPN) is a protein involved in various pathophysiological events. OPN has been studied as a secreted protein, but recent reports showed that OPN can be found in the cytoplasm and the nucleus. Therefore, some OPN molecules are not secreted and stay in cells. Such intracellular OPN (iOPN) has biological functions distinct from secreted OPN (sOPN). iOPN is involved in cytoskeletal rearrangement and in signal transduction pathways downstream of innate immune receptors, such as Toll-like receptors (TLRs), as an adaptor or scaffolding protein. Although sOPN and iOPN are generated from the same Opn mRNA species, biological outcomes mediated by two isoforms can be different. It would be necessary to delineate which isoform of OPN is responsible for pathophysiological events.
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