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Yang Y, Deng K, Jiang S, Guo X, Zhong Y, Wu B, Wei L. Punicalagin ameliorates lipopolysaccharide-induced inflammatory response in dental pulp cells via inhibition of the NF-κB/Wnt5a-ROR2 pathway. Immunopharmacol Immunotoxicol 2025; 47:317-327. [PMID: 39994845 DOI: 10.1080/08923973.2025.2470343] [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: 06/14/2024] [Accepted: 02/13/2025] [Indexed: 02/26/2025]
Abstract
INTRODUCTION Punicalagin (PCG) is a major polyphenolic component with potent anti-inflammatory, anti-atherogenic, anti-cancer, and antioxidant activities. This study aimed to investigate the impact and underlying mechanisms of PCG on lipopolysaccharide (LPS)-induced dental pulpitis. METHODS A rat pulpitis model was constructed, and the infected pulp was covered with a PCG collagen sponge. In vitro, dental pulp cells (DPCs) were isolated, and the effects of LPS and PCG on cell viability were assessed. The expression levels of inflammation-related factors were investigated by qRT-PCR and ELISA. The Nuclear Factor kappa B (NF-κB) transcription factors and Wnt family member 5a-Receptor tyrosine kinase like Orphan Receptor 2 (Wnt5a-ROR2) levels were evaluated by immunofluorescence staining and Western blotting. RESULTS We demonstrated that the PCG collagen sponge effectively reduced the infiltration of inflammatory cells in the pulp. PCG significantly alleviated the inflammatory response by reducing the mRNA expression levels of IL-1β, IL-6, IL-8, ICAM-1, and VCAM-1 and the secretion of IL-6 and IL-8 in a concentration-dependent manner. Immunofluorescence staining showed that the activation of the NF-κB pathway was hindered by PCG, which affected with the nuclear translocation of P65. PCG reduced the phosphorylation levels of P65 and IκBα and suppressed the expression levels of Wnt5a and ROR2 induced by LPS. The NF-κB inhibitor Bay11-7082 reduced the activation of the NF-κB/Wnt5a-ROR2 pathway and the inflammatory response; the application of PCG significantly augmented this inhibitory effect. DISCUSSION PCG demonstrated an anti-inflammatory effect in LPS-induced DPCs by targeting the NF-κB/Wnt5a-ROR2 signaling pathway.
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Affiliation(s)
- Yumeng Yang
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, China
- School of Stomatology, Southern Medical University, Guangzhou, China
| | - Ke Deng
- Division of Periodontology and Implant Dentistry, Faculty of Dentistry, The University of Hong Kong, Hong Kong SAR, China
| | - Shan Jiang
- Shenzhen Clinical College of Stomatology, School of Stomatology, Southern Medical University, Shenzhen, China
- Shenzhen Stomatology Hospital (Pingshan) of Southern Medical University, Shenzhen, China
| | - Xiaolan Guo
- School of Stomatology, Southern Medical University, Guangzhou, China
| | - Yiming Zhong
- School of Stomatology, Southern Medical University, Guangzhou, China
| | - Buling Wu
- Shenzhen Clinical College of Stomatology, School of Stomatology, Southern Medical University, Shenzhen, China
- Shenzhen Stomatology Hospital (Pingshan) of Southern Medical University, Shenzhen, China
| | - Liu Wei
- Shenzhen Clinical College of Stomatology, School of Stomatology, Southern Medical University, Shenzhen, China
- Shenzhen Stomatology Hospital (Pingshan) of Southern Medical University, Shenzhen, China
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Jurić I, Kelam N, Racetin A, Filipović N, Čarić D, Rošin M, Vukojević K. WNT Signaling Factors as Potential Synovial Inflammation Moderators in Patients with Hip Osteoarthritis. Biomedicines 2025; 13:995. [PMID: 40299569 PMCID: PMC12025112 DOI: 10.3390/biomedicines13040995] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2025] [Revised: 04/17/2025] [Accepted: 04/18/2025] [Indexed: 05/01/2025] Open
Abstract
Background: The main feature of osteoarthritis (OA) is the deterioration of articular cartilage, but numerous studies have demonstrated the role of synovial inflammation in the early stages of the disease, leading to further progression of OA. The WNT signaling pathway is involved in numerous activities in joint tissue, but there is a lack of evidence considering the role of WNT in OA synovitis. Our research aims to investigate the expression of WNT Family Member 5A/B (WNT5A/B), β-catenin, acetyl-α-tubulin, Dishevelled-1 (DVL-1), and Inversin (INV) in the synovial membrane of osteoarthritis (OA) hips. Methods: The immunohistochemical expressions of the aforementioned proteins in the synovial membrane were analyzed and compared with samples of control group participants with fractured femoral necks. Results: The immunoexpression of acetyl-α-tubulin was significantly increased in the intima (p < 0.0001) and subintima (p < 0.0001) of the group with OA compared with the intima and subintima of the control group. At the same time, acetyl-α-tubulin was also more highly expressed in the intima of the OA group than in the subintima of the OA group (p < 0.05); we found the same expression pattern in the control group (p < 0.0001). The differential analysis of the GEO dataset did not show significant differences between the osteoarthritis (OA) and control groups in the expression of TUBA1A. β-catenin was significantly increased in the subintima (p < 0.01) of the group with OA compared to the subintima of the control group. WNT expression has significantly higher positivity in the subintima than in the intima, especially in the control group (p < 0.01). WNT5A and WNT5B were significantly down-regulated in OA compared to the control in the differential analysis of the GEO dataset. The expression of INV and DVL-1 in our study and the differential analysis of the GEO dataset did not differ significantly between the osteoarthritis (OA) and control groups. Conclusions: Based on our results, we suggest that acetyl-α-tubulin and β-catenin might be involved in synovial membrane inflammation in OA and serve as potential therapeutic targets.
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Affiliation(s)
- Ivana Jurić
- Department of Emergency Medicine, University Hospital of Split, Spinciceva 1, 21000 Split, Croatia;
| | - Nela Kelam
- Department of Anatomy, Histology and Embryology, University of Split School of Medicine, Soltanska 2, 21000 Split, Croatia; (N.K.); (A.R.); (N.F.)
| | - Anita Racetin
- Department of Anatomy, Histology and Embryology, University of Split School of Medicine, Soltanska 2, 21000 Split, Croatia; (N.K.); (A.R.); (N.F.)
| | - Natalija Filipović
- Department of Anatomy, Histology and Embryology, University of Split School of Medicine, Soltanska 2, 21000 Split, Croatia; (N.K.); (A.R.); (N.F.)
| | - Davor Čarić
- Surgery Department, Orthopaedics and Traumatology Division, University Hospital of Split, Spinciceva 1, 21000 Split, Croatia; (D.Č.); (M.R.)
| | - Matko Rošin
- Surgery Department, Orthopaedics and Traumatology Division, University Hospital of Split, Spinciceva 1, 21000 Split, Croatia; (D.Č.); (M.R.)
| | - Katarina Vukojević
- Department of Anatomy, Histology and Embryology, University of Split School of Medicine, Soltanska 2, 21000 Split, Croatia; (N.K.); (A.R.); (N.F.)
- Center for Translational Research in Biomedicine, University of Split School of Medicine, Soltanska 2, 21000 Split, Croatia
- Mediterranean Institute for Life Sciences, University of Split, Meštrovićevo Šetalište 45, 21000 Split, Croatia
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Yu XH, Guo XN, Li K, Li JW, Wang K, Wang D, Liu BC. The Role of Wnt5a in Inflammatory Diseases. Immunology 2025; 174:203-212. [PMID: 39668514 DOI: 10.1111/imm.13882] [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: 06/22/2024] [Revised: 10/08/2024] [Accepted: 11/22/2024] [Indexed: 12/14/2024] Open
Abstract
Wnt5a plays an important role in cell development and maturation and is closely associated with various diseases, such as malignant tumours, metabolic disorders, fibrosis, growth and development. Recent studies have shown that Wnt5a expression and signal transduction are strongly involved in the inflammatory response. This study comprehensively reviewed the latest research progress on the association between Wnt5a and several inflammatory diseases, such as sepsis, asthma, chronic obstructive pulmonary disease, tuberculosis, rheumatoid arthritis, atherosclerosis and psoriasis vulgare. We elucidated the mechanism by which the Wnt5a protein is involved in the pathogenesis of these diseases, providing a basis for the prevention and treatment of inflammatory diseases.
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Affiliation(s)
- Xin-Hua Yu
- Department of Pediatrics, Bishan Hospital of Chongqing Medical University, Chongqing, China
| | - Xin-Ning Guo
- Department of Cardiology, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Kui Li
- Department of Respiratory and Critical Care Medicine, Bishan Hospital of Chongqing Medical University, Chongqing, China
| | - Jia-Wei Li
- Department of Respiratory and Critical Care Medicine, Bishan Hospital of Chongqing Medical University, Chongqing, China
| | - Kaijin Wang
- Department of Respiratory and Critical Care Medicine, Bishan Hospital of Chongqing Medical University, Chongqing, China
| | - Dan Wang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Bi-Cui Liu
- Department of Respiratory and Critical Care Medicine, Bishan Hospital of Chongqing Medical University, Chongqing, China
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Huang S, Xu X, Guo J, Li Z, Wu Y, Liu Y, Sun Q, Wang S, Yan H, Su Y, Guo W. Single-Cell Transcriptome Decoding Umbilical Cord-Derived Mesenchymal Stem Cell Heterogeneity Reveals a Unique IL1R1 HighPDGFRA High Ultroser-G-MSC With Osteogenesis and Chondrogenesis Signatures. J Cell Physiol 2025; 240:e70004. [PMID: 39956958 DOI: 10.1002/jcp.70004] [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: 07/29/2024] [Revised: 01/07/2025] [Accepted: 01/13/2025] [Indexed: 02/18/2025]
Abstract
The heterogeneity of human umbilical cord mesenchymal stem cells (hUC-MSCs) is culturing-dependent, resulting in functional non-uniformness. To achieve the best clinical benefit, a comprehensive understanding of the origin of the heterogeneity in different culture systems can identify functional subgroups to direct the precise application of hUC-MSCs. Here, we create a single-cell transcriptome atlas of hUC-MSC in different culture systems for the identification of a subgroup of Ultroser-G-MSCs with high osteogenic and chondrogenic potentials featured by high expressions of IL1R1 and PDGFRA. Further experimental validations surprisingly reveal that IL1R1highPDGFRAhigh Ultroser-G-MSCs possess advantages over "traditional" hUC-MSCs in the treatments of modeled osteoarthritis, leading to a cell-cell communication network centered in Clusters 0 and 2. Moreover, we found that Wnt5 signaling is the key pathway for the dynamic transformation of osteogenic and chondrogenic phenotypes in hUC-MSC. Overall, the present study paves the way for the clarification of heterogenetic nature of hUC-MSC in different culture systems for the selection of optimal MSC types to achieve the precision on clinical treatments.
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Affiliation(s)
- Shihao Huang
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Xinyu Xu
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Jiaqi Guo
- Jiangsu Renocell Biotech Co. Ltd., Nanjing, China
| | - Zhuolan Li
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Yanlin Wu
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Yuanyuan Liu
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Qinyi Sun
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Sihan Wang
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Huilin Yan
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Yueyan Su
- Jiangsu Renocell Biotech Co. Ltd., Nanjing, China
| | - Wei Guo
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
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Willis AB, Zelikovich AS, Sufit R, Ajroud-Driss S, Vandenborne K, Demonbreun AR, Batra A, Walter GA, McNally EM. Serum protein and imaging biomarkers after intermittent steroid treatment in muscular dystrophy. Sci Rep 2024; 14:28745. [PMID: 39567576 PMCID: PMC11579281 DOI: 10.1038/s41598-024-79024-8] [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: 04/15/2024] [Accepted: 11/04/2024] [Indexed: 11/22/2024] Open
Abstract
Weekly Steroids in Muscular Dystrophy (WSiMD) was a pilot study to evaluate once weekly prednisone in patients with Limb Girdle and Becker muscular dystrophy (LGMD and BMD, respectively). At study endpoint, there were trends towards increased lean mass, reduced fat mass, reduced creatine kinase and improved motor function. The investigation was motivated by studies in mouse muscular dystrophy models in which once weekly glucocorticoid exposure enhanced muscle strength and reduced fibrosis. WSiMD participants provided blood samples for aptamer serum profiling at baseline and after 6 months of weekly steroids. A subset completed magnetic resonance (MR) evaluation of muscle at study onset and endpoint. At baseline compared to age and sex-matched healthy controls, the aggregate serum protein profile in the WSiMD cohort was dominated by muscle proteins, reflecting leak of muscle proteins into serum. Disease status produced more proteins differentially present in serum compared to steroid-treatment effect. Nonetheless, a response to prednisone was discernable in the WSiMD cohort, even at this low dose. Glucocorticoids decreased muscle proteins and increased certain immune process- and matrix-associated proteins. Muscle MR fat fraction showed trends with functional status. The prednisone-responsive markers could be used in larger trial of prednisone efficacy.
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Affiliation(s)
- Alexander B Willis
- Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, 303 E Superior SQ 5-516, Chicago, IL, 60611, USA
| | - Aaron S Zelikovich
- Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, 303 E Superior SQ 5-516, Chicago, IL, 60611, USA
| | - Robert Sufit
- Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Senda Ajroud-Driss
- Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Krista Vandenborne
- Department of Physical Therapy, University of Florida, Gainesville, FL, USA
| | - Alexis R Demonbreun
- Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, 303 E Superior SQ 5-516, Chicago, IL, 60611, USA
- Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA
| | - Abhinandan Batra
- Department of Physical Therapy, University of Louisiana at Monroe, Monroe, LA, USA
| | - Glenn A Walter
- Department of Physiology and Aging, University of Florida, Gainesville, FL, USA
| | - Elizabeth M McNally
- Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, 303 E Superior SQ 5-516, Chicago, IL, 60611, USA.
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Li J, Hu H, Fu P, Yang Q, Wang P, Gao X, Yang J, Gun S, Huang X. Pig Milk Exosome Packaging ssc-miR-22-3p Alleviates Pig Intestinal Epithelial Cell Injury and Inflammatory Response by Targeting MAPK14. Int J Mol Sci 2024; 25:10715. [PMID: 39409044 PMCID: PMC11476862 DOI: 10.3390/ijms251910715] [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: 09/12/2024] [Revised: 10/01/2024] [Accepted: 10/03/2024] [Indexed: 10/19/2024] Open
Abstract
Inflammatory diseases of the intestinal tract in piglets severely impair the economic performance of pig farms. Pig milk exosomes can encapsulate miRNAs which can then enter the piglet intestine to play an immunomodulatory role. Previously, we comparatively analyzed and identified exosomal miRNAs in the colostrum and mature milk of Bamei and Landrace pigs, and we screened for ssc-miR-22-3p, which is associated with inflammation and immune response; however, the role played by ssc-miR-22-3p in the immune response in IPEC-J2 cells is not yet clear. In this study, we first constructed a pig intestinal inflammatory response model using Lipopolysaccharide (LPS) and Polyinosinic-polycytidylic acid (Poly (I:C)), and we investigated the role of ssc-miR-22-3p targeting MAPK14 in the regulation of LPS and Poly (I:C)-induced inflammatory injury in IPEC-J2 cells by RT-qPCR, cell counting kit-8 (CCK-8), EdU staining, lactate dehydrogenase (LDH) activity assay, and dual luciferase reporter gene assay. We successfully established LPS and Poly (I:C)-induced cell damage models in IPEC-J2 cells. The immune response of IPEC-J2 cells was stimulated by induction of IPEC-J2 cells at 10 μg/mL LPS and 20 μg/mL Poly (I:C) for 24 h. Overexpression of ssc-miR-22-3p decreased cytokine expression and promoted cell viability and proliferation. The functional enrichment analysis revealed that ssc-miR-22-3p targets genes enriched in the pathways of negative regulation of inflammatory response and bacterial invasion of epithelial cells. The validity of the binding site of ssc-miR-22-3p to MAPK14 was tested by a dual luciferase reporter gene. Pig milk exosome ssc-miR-22-3p promotes cell viability and proliferation by targeting MAPK14, and it alleviates LPS and Poly (I:C)-induced inflammatory responses in IPEC-J2 cells.
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Affiliation(s)
- Jie Li
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou 730070, China; (J.L.)
| | - Huihui Hu
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou 730070, China; (J.L.)
| | - Panpan Fu
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou 730070, China; (J.L.)
| | - Qiaoli Yang
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou 730070, China; (J.L.)
| | - Pengfei Wang
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou 730070, China; (J.L.)
| | - Xiaoli Gao
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou 730070, China; (J.L.)
| | - Jiaojiao Yang
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou 730070, China; (J.L.)
| | - Shuangbao Gun
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou 730070, China; (J.L.)
- Gansu Research Center for Swine Production Engineering and Technology, Lanzhou 730070, China
| | - Xiaoyu Huang
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou 730070, China; (J.L.)
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Inoue Y, Kumagai K, Ishikawa K, Kato I, Kusaba Y, Naka T, Nagashima K, Choe H, Ike H, Kobayashi N, Inaba Y. Increased Wnt5a/ROR2 signaling is associated with chondrogenesis in meniscal degeneration. J Orthop Res 2024; 42:1880-1889. [PMID: 38440852 DOI: 10.1002/jor.25825] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 02/05/2024] [Accepted: 02/19/2024] [Indexed: 03/06/2024]
Abstract
The aim of the present study was to investigate the association between chondrogenic differentiation and Wnt signal expression in the degenerative process of the human meniscus. Menisci were obtained from patients with and without knee osteoarthritis (OA), and degeneration was histologically assessed using a grading system. Immunohistochemistry, real-time polymerase chain reaction (PCR), and Western blot analysis were performed to examine the expressions of chondrogenic markers and of the components of Wnt signaling. Histological analyses showed that meniscal degeneration involved a transition from a fibroblastic to a chondrogenic phenotype with the upregulation of SOX9, collagen type II, collagen type XI, and aggrecan, which were associated with increased Wnt5a and ROR2 and decreased TCF7 expressions. OA menisci showed significantly higher expressions of Wnt5a and ROR2 and significantly lower expressions of AXIN2 and TCF7 than non-OA menisci on real-time PCR and Western blot analysis. These results potentially demonstrated that increased expression of Wnt5a/ROR2 signaling promoted chondrogenesis with decreased expression in downstream Wnt/β-catenin signaling. This study provides insights into the role of Wnt signaling in the process of meniscal degeneration, shifting to a chondrogenic phenotype. The findings suggested that the increased expression of Wnt5a/ROR2 and decreased expression of the downstream target of Wnt/β-catenin signaling are associated with chondrogenesis in meniscal degeneration.
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Affiliation(s)
- Yusuke Inoue
- Department of Orthopaedic Surgery and Muscloskeletal Science, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Ken Kumagai
- Department of Orthopaedic Surgery and Muscloskeletal Science, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Kimi Ishikawa
- Department of Orthopaedic Surgery and Muscloskeletal Science, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Ikuma Kato
- Department of Molecular Pathology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Youhei Kusaba
- Department of Orthopaedic Surgery and Muscloskeletal Science, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Takuma Naka
- Department of Orthopaedic Surgery and Muscloskeletal Science, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Kiyotaka Nagashima
- Department of Orthopaedic Surgery and Muscloskeletal Science, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Hyonmin Choe
- Department of Orthopaedic Surgery and Muscloskeletal Science, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Hiroyuki Ike
- Department of Orthopaedic Surgery and Muscloskeletal Science, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Naomi Kobayashi
- Department of Orthopaedic Surgery, Yokohama City University Medical Center, Yokohama, Japan
| | - Yutaka Inaba
- Department of Orthopaedic Surgery and Muscloskeletal Science, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
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Willis AB, Zelikovich AS, Sufit R, Ajroud-Driss S, Vandenborne K, Demonbreun AR, Batra A, Walter GA, McNally EM. Serum protein and imaging biomarkers after intermittent steroid treatment in muscular dystrophy. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2024.06.14.24308858. [PMID: 38947030 PMCID: PMC11213068 DOI: 10.1101/2024.06.14.24308858] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/02/2024]
Abstract
Background Weekly Steroids in Muscular Dystrophy (WSiMD) was a pilot study to evaluate once weekly prednisone in patients with Limb Girdle and Becker muscular dystrophy (LGMD and BMD, respectively). At study endpoint, there were trends towards increased lean mass, reduced fat mass, reduced creatine kinase and improved motor function. The investigation was motivated by studies in mouse muscular dystrophy models in which once weekly glucocorticoid exposure enhanced muscle strength and reduced fibrosis. Methods WSiMD participants provided blood samples for aptamer serum profiling at baseline and after 6 months of weekly steroids. A subset completed magnetic resonance (MR) evaluation of muscle at study onset and endpoint. Results/Conclusions At baseline compared to age and sex-matched healthy controls, the aggregate serum protein profile in the WSiMD cohort was dominated by muscle proteins, reflecting leak of muscle proteins into serum. Disease status produced more proteins differentially present in serum compared to steroid-treatment effect. Nonetheless, a response to prednisone was discernable in the WSiMD cohort, even at this low dose. Glucocorticoids downregulated muscle proteins and upregulated certain immune process- and matrix-associated proteins. Muscle MR fat fraction showed trends with functional status. The prednisone-responsive markers could be used in larger trial of prednisone efficacy.
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Affiliation(s)
- Alexander B. Willis
- Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Aaron S. Zelikovich
- Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Robert Sufit
- Dept of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL
| | - Senda Ajroud-Driss
- Dept of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL
| | | | - Alexis R. Demonbreun
- Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
- Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Abhinandan Batra
- Department of Physical Therapy, University of Louisiana at Monroe, Monroe, LA
| | - Glenn A. Walter
- Department of Physiology and Aging, University of Florida, Gainesville, FL
| | - Elizabeth M. McNally
- Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
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Zhang M, Liu Q, Meng H, Duan H, Liu X, Wu J, Gao F, Wang S, Tan R, Yuan J. Ischemia-reperfusion injury: molecular mechanisms and therapeutic targets. Signal Transduct Target Ther 2024; 9:12. [PMID: 38185705 PMCID: PMC10772178 DOI: 10.1038/s41392-023-01688-x] [Citation(s) in RCA: 160] [Impact Index Per Article: 160.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Revised: 08/29/2023] [Accepted: 10/18/2023] [Indexed: 01/09/2024] Open
Abstract
Ischemia-reperfusion (I/R) injury paradoxically occurs during reperfusion following ischemia, exacerbating the initial tissue damage. The limited understanding of the intricate mechanisms underlying I/R injury hinders the development of effective therapeutic interventions. The Wnt signaling pathway exhibits extensive crosstalk with various other pathways, forming a network system of signaling pathways involved in I/R injury. This review article elucidates the underlying mechanisms involved in Wnt signaling, as well as the complex interplay between Wnt and other pathways, including Notch, phosphatidylinositol 3-kinase/protein kinase B, transforming growth factor-β, nuclear factor kappa, bone morphogenetic protein, N-methyl-D-aspartic acid receptor-Ca2+-Activin A, Hippo-Yes-associated protein, toll-like receptor 4/toll-interleukine-1 receptor domain-containing adapter-inducing interferon-β, and hepatocyte growth factor/mesenchymal-epithelial transition factor. In particular, we delve into their respective contributions to key pathological processes, including apoptosis, the inflammatory response, oxidative stress, extracellular matrix remodeling, angiogenesis, cell hypertrophy, fibrosis, ferroptosis, neurogenesis, and blood-brain barrier damage during I/R injury. Our comprehensive analysis of the mechanisms involved in Wnt signaling during I/R reveals that activation of the canonical Wnt pathway promotes organ recovery, while activation of the non-canonical Wnt pathways exacerbates injury. Moreover, we explore novel therapeutic approaches based on these mechanistic findings, incorporating evidence from animal experiments, current standards, and clinical trials. The objective of this review is to provide deeper insights into the roles of Wnt and its crosstalk signaling pathways in I/R-mediated processes and organ dysfunction, to facilitate the development of innovative therapeutic agents for I/R injury.
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Affiliation(s)
- Meng Zhang
- The Collaborative Innovation Center, Jining Medical University, Jining, Shandong, 272067, China
| | - Qian Liu
- Clinical Medical College, Jining Medical University, Jining, Shandong, 272067, China
| | - Hui Meng
- Clinical Medical College, Jining Medical University, Jining, Shandong, 272067, China
| | - Hongxia Duan
- Clinical Medical College, Jining Medical University, Jining, Shandong, 272067, China
| | - Xin Liu
- Second Clinical Medical College, Jining Medical University, Jining, Shandong, 272067, China
| | - Jian Wu
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Fei Gao
- The Collaborative Innovation Center, Jining Medical University, Jining, Shandong, 272067, China
- Institute of Zoology, Chinese Academy of Sciences, Beijing, China
| | - Shijun Wang
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
| | - Rubin Tan
- Department of Physiology, Basic medical school, Xuzhou Medical University, Xuzhou, 221004, China.
| | - Jinxiang Yuan
- The Collaborative Innovation Center, Jining Medical University, Jining, Shandong, 272067, China.
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Huang Y, Xue Q, Chang J, Wang X, Miao C. Wnt5a: A promising therapeutic target for inflammation, especially rheumatoid arthritis. Cytokine 2023; 172:156381. [PMID: 37806072 DOI: 10.1016/j.cyto.2023.156381] [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: 04/06/2023] [Revised: 06/05/2023] [Accepted: 09/22/2023] [Indexed: 10/10/2023]
Abstract
BACKGROUND Wnt5a is a member of the Wnt protein family, which acts on classical or multiple non-classical Wnt signaling pathways by binding to different receptors. The expression regulation and signal transduction of Wnt5a is closely related to the inflammatory response. Abnormal activation of Wnt5a signaling is an important part of inflammation and rheumatoid arthritis (RA). OBJECTIVES This paper mainly focuses on Wnt5a protein and its mediated signaling pathway, summarizes the latest research progress of Wnt5a in the pathological process of inflammation and RA, and looks forward to the main directions of Wnt5a in RA research, aiming to provide a theoretical basis for the prevention and treatment of RA diseases by targeting Wnt5a. RESULTS Wnt5a is highly expressed in activated blood vessels, histocytes and synoviocytes in inflammatory diseases such as sepsis, sepsis, atherosclerosis and rheumatoid arthritis. It mediates the production of pro-inflammatory cytokines and chemokines, regulates the migration and recruitment of various immune effector cells, and thus participates in the inflammatory response. Wnt5a plays a pathological role in synovial inflammation and bone destruction of RA, and may be an important clinical therapeutic target for RA. CONCLUSION Wnt5a is involved in the pathological process of inflammation and interacts with inflammatory factors. Wnt5a may be a new target for regulating the progression of RA disease and intervening therapy because of its multi-modal effects on the etiology of RA, especially as a regulator of osteoclast activity and inflammation.
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Affiliation(s)
- Yurong Huang
- Department of Pharmacology, School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, China
| | - Qiuyun Xue
- Department of Pharmacology, School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, China
| | - Jun Chang
- Department of Orthopaedics, the First Affiliated Hospital, Anhui Medical University, Hefei 230032, China; Anhui Public Health Clinical Center, Hefei, China.
| | - Xiao Wang
- Department of Clinical Nursing, School of Nursing, Anhui University of Chinese Medicine, Hefei, China.
| | - Chenggui Miao
- Department of Pharmacology, School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, China.
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Riekert M, Almanzar G, Schmalzing M, Schütze N, Jakob F, Prelog M. Mesenchymal stem cells modulate IL-17 and IL-9 production induced by Th17-inducing cytokine conditions in autoimmune arthritis: an explorative analysis. Adv Rheumatol 2023; 63:37. [PMID: 37525265 DOI: 10.1186/s42358-023-00317-z] [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: 12/08/2022] [Accepted: 07/19/2023] [Indexed: 08/02/2023] Open
Abstract
BACKGROUND The importance of proinflammatory T-cells and their cytokine production in patients with autoimmune arthritis has been widely described. Due to their immunomodulatory properties, mesenchymal stem cells (MSCs) have come into focus as a potential therapeutic concept. The aim of this study was to investigate the influence of MSCs on the phenotype, cytokine profile, and functionality of naive and non-naive CD4+ T-cells from healthy donors (HD) and patients with autoimmune arthritis under Th17-cytokine polarizing conditions in an explorative way using a transwell system prohibiting any cell-cell-contact. METHODS Magnetically isolated naive and non-naive CD4+ T-cells were stimulated under Th17-polarizing proinflammatory cytokine conditions in presence and absence of bone marrow derived mesenchymal stromal cells (MSCs). After an incubation period of 6 days, the proportions of the T-cell subpopulations TEMRA (CD45RA+CD27-), memory (CD45RA-CD27+), effector (CD45RA-CD27-) and naive cells (CD45RA+CD27+) were determined. Quantitative immunofluorescence intensity was used as a measure for IL-9, IL-17 and IFN-γ production in each subpopulation. RESULTS In isolated naive CD4+ T-cells from HD and patients, MSCs suppressed the differentiation of naive towards an effector phenotype while memory and naive cells showed higher percentages in culture with MSCs. In patients, MSCs significantly decreased the proportion of IL-9 and IL-17 producing effector T-cells. MSCs also reduced IFN-γ production in the naive and memory phenotype from HD. CONCLUSION The results of the study indicate significant immunomodulatory properties of MSCs, as under Th17-polarizing conditions MSCs are still able to control T-cell differentiation and proinflammatory cytokine production in both HD and patients with autoimmune arthritis.
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Affiliation(s)
- Maximilian Riekert
- Department of Pediatrics, University Hospital Wuerzburg, Wuerzburg, Germany.
- Department of Oral and Craniomaxillofacial and Plastic Surgery, Faculty of Medicine and University Hospital Cologne, University of Cologne, Kerpener Straße 62, 50924, Cologne, Germany.
| | - Giovanni Almanzar
- Department of Pediatrics, University Hospital Wuerzburg, Wuerzburg, Germany
| | - Marc Schmalzing
- Department of Internal Medicine II, University Hospital of Wuerzburg, Wuerzburg, Germany
| | - Norbert Schütze
- Orthopedic Clinic, Orthopedic Center for Musculoskeletal Research, University of Wuerzburg, Wuerzburg, Germany
| | - Franz Jakob
- Orthopedic Clinic, Orthopedic Center for Musculoskeletal Research, University of Wuerzburg, Wuerzburg, Germany
| | - Martina Prelog
- Department of Pediatrics, University Hospital Wuerzburg, Wuerzburg, Germany
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12
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cRel and Wnt5a/Frizzled 5 Receptor-Mediated Inflammatory Regulation Reveal Novel Neuroprotectin D1 Targets for Neuroprotection. Cell Mol Neurobiol 2023; 43:1077-1096. [PMID: 35622188 PMCID: PMC10006067 DOI: 10.1007/s10571-022-01231-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Accepted: 05/10/2022] [Indexed: 11/03/2022]
Abstract
Wnt5a triggers inflammatory responses and damage via NFkB/p65 in retinal pigment epithelial (RPE) cells undergoing uncompensated oxidative stress (UOS) and in experimental ischemic stroke. We found that Wnt5a-Clathrin-mediated uptake leads to NFkB/p65 activation and that Wnt5a is secreted in an exosome-independent fashion. We uncovered that docosahexaenoic acid (DHA) and its derivative, Neuroprotectin D1 (NPD1), upregulate c-Rel expression that, as a result, blunts Wnt5a abundance by competing with NFkB/p65 on the Wnt5a promoter A. Wnt5a increases in ischemic stroke penumbra and blood, while DHA reduces Wnt5a abundance with concomitant neuroprotection. Peptide inhibitor of Wnt5a binding, Box5, is also neuroprotective. DHA-decreased Wnt5a expression is concurrent with a drop in NFkB-driven inflammatory cytokine expression, revealing mechanisms after stroke, as in RPE cells exposed to UOS. Limiting the Wnt5a activity via Box5 reduces stroke size, suggesting neuroprotection pertinent to onset and progression of retinal degenerations and stroke consequences. NPD1 disrupts Wnt5a feedback loop at two sites: (1) decreasing FZD5, thus Wnt5a internalization, and (2) by enhancing cREL activity, which competes with p65/NFkB downstream endocytosis. As a result, Wnt5a expression is reduced, and so is its inflammatory signaling in RPE cells and neurons in ischemic stroke.
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13
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Singla A, Reuter S, Taube C, Peters M, Peters K. The molecular mechanisms of remodeling in asthma, COPD and IPF with a special emphasis on the complex role of Wnt5A. Inflamm Res 2023; 72:577-588. [PMID: 36658268 PMCID: PMC10023767 DOI: 10.1007/s00011-023-01692-5] [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: 11/23/2022] [Revised: 11/28/2022] [Accepted: 01/09/2023] [Indexed: 01/20/2023] Open
Abstract
INTRODUCTION Chronic inflammatory lung diseases are a common cause of suffering and death. Chronic obstructive pulmonary disease (COPD) is the reason for 6% of all deaths worldwide. A total of 262 million people are affected by asthma and 461,000 people died in 2019. Idiopathic pulmonary fibrosis (IPF) is diagnosed in 3 million people worldwide, with an onset over the age of 50 with a mean survival of only 24-30 months. These three diseases have in common that remodeling of the lung tissue takes place, which is responsible for an irreversible decline of lung function. Pathological lung remodeling is mediated by a complex interaction of different, often misguided, repair processes regulated by a variety of mediators. One group of these, as has recently become known, are the Wnt ligands. In addition to their well-characterized role in embryogenesis, this group of glycoproteins is also involved in immunological and structural repair processes. Depending on the combination of the Wnt ligand with its receptors and co-receptors, canonical and noncanonical signaling cascades can be induced. Wnt5A is a mediator that is described mainly in noncanonical Wnt signaling and has been shown to play an important role in different inflammatory diseases and malignancies. OBJECTIVES In this review, we summarize the literature available regarding the role of Wnt5A as an immune modulator and its role in the development of asthma, COPD and IPF. We will focus specifically on what is known about Wnt5A concerning its role in the remodeling processes involved in the chronification of the diseases. CONCLUSION Wnt5A has been shown to be involved in all three inflammatory lung diseases. Since the ligand affects both structural and immunological processes, it is an interesting target for the treatment of lung diseases whose pathology involves a restructuring of the lung tissue triggered in part by an inflammatory immune response.
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Affiliation(s)
- Abhinav Singla
- Department of Pulmonary Medicine, University Medical Center Essen-Ruhrlandklinik, Essen, Germany
- Department of Molecular Immunology, Ruhr-University Bochum, Universitätsstraße 150, 44801, Bochum, Germany
| | - Sebastian Reuter
- Department of Pulmonary Medicine, University Medical Center Essen-Ruhrlandklinik, Essen, Germany
| | - Christian Taube
- Department of Pulmonary Medicine, University Medical Center Essen-Ruhrlandklinik, Essen, Germany
| | - Marcus Peters
- Department of Molecular Immunology, Ruhr-University Bochum, Universitätsstraße 150, 44801, Bochum, Germany.
| | - Karin Peters
- Department of Molecular Immunology, Ruhr-University Bochum, Universitätsstraße 150, 44801, Bochum, Germany
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Prajapati P, Doshi G. An Update on the Emerging Role of Wnt/β-catenin, SYK, PI3K/AKT, and GM-CSF Signaling Pathways in Rheumatoid Arthritis. Curr Drug Targets 2023; 24:1298-1316. [PMID: 38083893 DOI: 10.2174/0113894501276093231206064243] [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: 08/07/2023] [Revised: 10/14/2023] [Accepted: 11/14/2023] [Indexed: 01/06/2024]
Abstract
Rheumatoid arthritis is an untreatable autoimmune disorder. The disease is accompanied by joint impairment and anomalies, which negatively affect the patient's quality of life and contribute to a decline in manpower. To diagnose and treat rheumatoid arthritis, it is crucial to understand the abnormal signaling pathways that contribute to the disease. This understanding will help develop new rheumatoid arthritis-related intervention targets. Over the last few decades, researchers have given more attention to rheumatoid arthritis. The current review seeks to provide a detailed summary of rheumatoid arthritis, highlighting the basic description of the disease, past occurrences, the study of epidemiology, risk elements, and the process of disease progression, as well as the key scientific development of the disease condition and multiple signaling pathways and enumerating the most current advancements in discovering new rheumatoid arthritis signaling pathways and rheumatoid arthritis inhibitors. This review emphasizes the anti-rheumatoid effects of these inhibitors [for the Wnt/β-catenin, Phosphoinositide 3-Kinases (PI3K/AKT), Spleen Tyrosine Kinase (SYK), and Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) signaling pathways], illustrating their mechanism of action through a literature search, current therapies, and novel drugs under pre-clinical and clinical trials.
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Affiliation(s)
- Pradyuman Prajapati
- SVKM's Dr Bhanuben Nanavati College of Pharmacy, V.M. Road, Vile Parle (W), Mumbai, India
| | - Gaurav Doshi
- SVKM's Dr Bhanuben Nanavati College of Pharmacy, V.M. Road, Vile Parle (W), Mumbai, India
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15
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Zhu M, Yan X, Zhao Y, Xue H, Wang Z, Wu B, Li X, Shen Y. lncRNA LINC00284 promotes nucleus pulposus cell proliferation and ECM synthesis via regulation of the miR‑205‑3p/Wnt/β‑catenin axis. Mol Med Rep 2022; 25:179. [PMID: 35322864 PMCID: PMC8972274 DOI: 10.3892/mmr.2022.12695] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Accepted: 02/23/2022] [Indexed: 11/08/2022] Open
Abstract
Intervertebral disc degeneration (IDD) is a leading cause of degenerative spinal disease. Long non-coding RNA (lncRNA) LINC00284 is overexpressed in multiple types of cancer and promotes cancer cell proliferation and inhibits apoptosis; however, its role in human IDD and nucleus pulposus (NP) remain unclear. In the present study, intervertebral disc (IVD) tissues were collected from IDD patients for detection of LINC00284 expression using reverse transcription-quantitative PCR, the binding effect between miR-205-3p and LINC00284 was validated by dual-luciferase reporter assay. miR-205-3p and small interfering RNA (siRNA) was used for LINC00240 knockdown to investigate the proliferation, apoptosis of cells in the NP cells measured by Cell Counting Kit (CCK)-8 assay and Annexin V-FITC/Propidium Iodide (PI) staining with flow cytometry receptivity. IDD animal models were constructed for in vivo study of the role LINC00284 in IDD improvement. The results showed that LINC00284 expression was upregulated in IDD tissue and IL-1β-induced NP cells. LINC00284 knockdown resulted in an increase in IL-1β-induced NP cell proliferation, a decrease in apoptosis and matrix metalloproteinase-3 expression and an increase in expression of extracellular matrix (ECM) markers aggrecan and collagen II. In vivo experiments and histomorphometric analysis confirmed the protective effect of LINC00284 knockdown in IDD. LINC00284 was also shown to be a target of microRNA (miR)-205-3p, and there was a negative correlation between LINC00284 and miR-205-3p levels in IDD tissue. Additionally, LINC00284 knockdown or miR-205-3p upregulation resulted in inhibition of Wnt/β-catenin signaling and subsequent degradation of the ECM. The present study demonstrated that LINC00284 activated the Wnt/β-catenin signaling via sponging miR-205-3p, resulting in inhibition of NP cell proliferation and ECM synthesis. These results suggested that targeting LINC00284 to rescue miR-205-3p expression may be a potential method for IDD management.
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Affiliation(s)
- Min Zhu
- Department of Spine Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P.R. China
| | - Xiaoling Yan
- Chemotherapy Department, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Yin Zhao
- Department of Spine Surgery, Shanghai Changzheng Hospital, The Second Military Medical University, Shanghai 200003, P.R. China
| | - Huawei Xue
- Department of Spine Surgery, Nantong Third People's Hospital, Nantong, Jiangsu 226006, P.R. China
| | - Zhen Wang
- Department of Spine Surgery, Nantong Third People's Hospital, Nantong, Jiangsu 226006, P.R. China
| | - Bo Wu
- Department of Spine Surgery, Nantong Third People's Hospital, Nantong, Jiangsu 226006, P.R. China
| | - Xiangyang Li
- Department of Spine Surgery, Nantong Third People's Hospital, Nantong, Jiangsu 226006, P.R. China
| | - Yixin Shen
- Department of Spine Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P.R. China
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16
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Maeda K, Yoshida K, Nishizawa T, Otani K, Yamashita Y, Okabe H, Hadano Y, Kayama T, Kurosaka D, Saito M. Inflammation and Bone Metabolism in Rheumatoid Arthritis: Molecular Mechanisms of Joint Destruction and Pharmacological Treatments. Int J Mol Sci 2022; 23:2871. [PMID: 35270012 PMCID: PMC8911191 DOI: 10.3390/ijms23052871] [Citation(s) in RCA: 66] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 02/28/2022] [Accepted: 03/02/2022] [Indexed: 12/31/2022] Open
Abstract
Rheumatoid arthritis (RA) is an inflammatory disease characterized by a variety of symptoms and pathologies often presenting with polyarthritis. The primary symptom in the initial stage is joint swelling due to synovitis. With disease progression, cartilage and bone are affected to cause joint deformities. Advanced osteoarticular destruction and deformation can cause irreversible physical disabilities. Physical disabilities not only deteriorate patients' quality of life but also have substantial medical economic effects on society. Therefore, prevention of the progression of osteoarticular destruction and deformation is an important task. Recent studies have progressively improved our understanding of the molecular mechanism by which synovitis caused by immune disorders results in activation of osteoclasts; activated osteoclasts in turn cause bone destruction and para-articular osteoporosis. In this paper, we review the mechanisms of bone metabolism under physiological and RA conditions, and we describe the effects of therapeutic intervention against RA on bone.
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Affiliation(s)
- Kazuhiro Maeda
- Department of Orthopaedic Surgery, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, Japan; (T.N.); (Y.Y.); (H.O.); (Y.H.); (T.K.); (M.S.)
| | - Ken Yoshida
- Division of Rheumatology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, Japan; (K.Y.); (K.O.); (D.K.)
| | - Tetsuro Nishizawa
- Department of Orthopaedic Surgery, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, Japan; (T.N.); (Y.Y.); (H.O.); (Y.H.); (T.K.); (M.S.)
| | - Kazuhiro Otani
- Division of Rheumatology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, Japan; (K.Y.); (K.O.); (D.K.)
| | - Yu Yamashita
- Department of Orthopaedic Surgery, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, Japan; (T.N.); (Y.Y.); (H.O.); (Y.H.); (T.K.); (M.S.)
| | - Hinako Okabe
- Department of Orthopaedic Surgery, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, Japan; (T.N.); (Y.Y.); (H.O.); (Y.H.); (T.K.); (M.S.)
| | - Yuka Hadano
- Department of Orthopaedic Surgery, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, Japan; (T.N.); (Y.Y.); (H.O.); (Y.H.); (T.K.); (M.S.)
| | - Tomohiro Kayama
- Department of Orthopaedic Surgery, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, Japan; (T.N.); (Y.Y.); (H.O.); (Y.H.); (T.K.); (M.S.)
| | - Daitaro Kurosaka
- Division of Rheumatology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, Japan; (K.Y.); (K.O.); (D.K.)
| | - Mitsuru Saito
- Department of Orthopaedic Surgery, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, Japan; (T.N.); (Y.Y.); (H.O.); (Y.H.); (T.K.); (M.S.)
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17
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Vasiliadis ES, Evangelopoulos DS, Kaspiris A, Benetos IS, Vlachos C, Pneumaticos SG. The Role of Sclerostin in Bone Diseases. J Clin Med 2022; 11:806. [PMID: 35160258 PMCID: PMC8836457 DOI: 10.3390/jcm11030806] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Revised: 01/27/2022] [Accepted: 01/31/2022] [Indexed: 12/26/2022] Open
Abstract
Sclerostin has been identified as an important regulator of bone homeostasis through inhibition of the canonical Wnt-signaling pathway, and it is involved in the pathogenesis of many different skeletal diseases. Many studies have been published in the last few years regarding sclerostin's origin, regulation, and mechanism of action. The ongoing research emphasizes the potential therapeutic implications of sclerostin in many pathological conditions with or without skeletal involvement. Antisclerostin antibodies have recently been approved for the treatment of osteoporosis, and several animal studies and clinical trials are currently under way to evaluate the effectiveness of antisclerostin antibodies in the treatment of other than osteoporosis skeletal disorders and cancer with promising results. Understanding the exact role of sclerostin may lead to new therapeutic approaches for the treatment of skeletal disorders.
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Affiliation(s)
- Elias S. Vasiliadis
- 3rd Department of Orthopaedics, School of Medicine, National and Kapodistrian University of Athens, KAT Hospital, 16541 Athens, Greece; (D.-S.E.); (I.S.B.); (C.V.); (S.G.P.)
| | - Dimitrios-Stergios Evangelopoulos
- 3rd Department of Orthopaedics, School of Medicine, National and Kapodistrian University of Athens, KAT Hospital, 16541 Athens, Greece; (D.-S.E.); (I.S.B.); (C.V.); (S.G.P.)
| | - Angelos Kaspiris
- Laboratory of Molecular Pharmacology, Division for Orthopaedic Research, School of Health Sciences, University of Patras, 26504 Rion, Greece;
| | - Ioannis S. Benetos
- 3rd Department of Orthopaedics, School of Medicine, National and Kapodistrian University of Athens, KAT Hospital, 16541 Athens, Greece; (D.-S.E.); (I.S.B.); (C.V.); (S.G.P.)
| | - Christos Vlachos
- 3rd Department of Orthopaedics, School of Medicine, National and Kapodistrian University of Athens, KAT Hospital, 16541 Athens, Greece; (D.-S.E.); (I.S.B.); (C.V.); (S.G.P.)
| | - Spyros G. Pneumaticos
- 3rd Department of Orthopaedics, School of Medicine, National and Kapodistrian University of Athens, KAT Hospital, 16541 Athens, Greece; (D.-S.E.); (I.S.B.); (C.V.); (S.G.P.)
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González-Quintanilla D, Abásolo N, Astudillo P. Wnt Signaling in Periodontal Disease. FRONTIERS IN DENTAL MEDICINE 2021. [DOI: 10.3389/fdmed.2021.763308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Periodontitis is a multifactorial and chronic condition associated with the formation of a dysbiotic biofilm, leading to a pro-inflammatory environment that can modulate cell signaling. The Wnt pathway plays fundamental roles during homeostasis and disease, and emerging evidence suggests its involvement in the maintenance of the periodontium and the development of periodontitis. Here, we summarize the role of the Wnt/β-catenin and non-canonical Wnt signaling pathways in periodontitis. The accumulated data suggests specific roles for each branch of the Wnt pathway. Wnt5a emerges as a critical player promoting periodontal ligament remodeling and impairing regenerative responses modulated by the Wnt/β-catenin pathway, such as alveolar bone formation. Collectively, the evidence suggests that achieving a proper balance between the Wnt/β-catenin and non-canonical pathways, rather than their independent modulation, might contribute to controlling the progression and severity of the periodontal disease.
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19
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Li R, Salehi-Rad R, Crosson W, Momcilovic M, Lim RJ, Ong SL, Huang ZL, Zhang T, Abascal J, Dumitras C, Jing Z, Park SJ, Krysan K, Shackelford DB, Tran LM, Liu B, Dubinett SM. Inhibition of Granulocytic Myeloid-Derived Suppressor Cells Overcomes Resistance to Immune Checkpoint Inhibition in LKB1-Deficient Non-Small Cell Lung Cancer. Cancer Res 2021; 81:3295-3308. [PMID: 33853830 PMCID: PMC8776246 DOI: 10.1158/0008-5472.can-20-3564] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 03/08/2021] [Accepted: 04/12/2021] [Indexed: 01/19/2023]
Abstract
LKB1 inactivating mutations are commonly observed in patients with KRAS-mutant non-small cell lung cancer (NSCLC). Although treatment of NSCLC with immune checkpoint inhibitors (ICI) has resulted in improved overall survival in a subset of patients, studies have revealed that co-occurring KRAS/LKB1 mutations drive primary resistance to ICIs in NSCLC. Effective therapeutic options that overcome ICI resistance in LKB1-mutant NSCLC are limited. Here, we report that loss of LKB1 results in increased secretion of the C-X-C motif (CXC) chemokines with an NH2-terminal Glu-Leu-Arg (ELR) motif in premalignant and cancerous cells, as well as in genetically engineered murine models (GEMM) of NSCLC. Heightened levels of ELR+ CXC chemokines in LKB1-deficient murine models of NSCLC positively correlated with increased abundance of granulocytic myeloid-derived suppressor cells (G-MDSC) locally within the tumor microenvironment and systemically in peripheral blood and spleen. Depletion of G-MDSCs with antibody or functional inhibition via all-trans-retinoic acid (ATRA) led to enhanced antitumor T-cell responses and sensitized LKB1-deficent murine tumors to PD-1 blockade. Combination therapy with anti-PD-1 and ATRA improved local and systemic T-cell proliferation and generated tumor-specific immunity. Our findings implicate ELR+ CXC chemokine-mediated enrichment of G-MDSCs as a potential mediator of immunosuppression in LKB1-deficient NSCLC and provide a rationale for using ATRA in combination with anti-PD-1 therapy in patients with LKB1-deficient NSCLC refractory to ICIs. SIGNIFICANCE: These findings show that accumulation of myeloid-derived suppressor cells in LKB1-deficient non-small cell lung cancer can be overcome via treatment with all-trans-retinoic acid, sensitizing tumors to immunotherapy.
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Affiliation(s)
- Rui Li
- Department of Medicine, Division of Pulmonary and Critical Care, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, 43-229 CHS, Los Angeles, CA 90095-1690, USA
| | - Ramin Salehi-Rad
- Department of Medicine, Division of Pulmonary and Critical Care, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, 43-229 CHS, Los Angeles, CA 90095-1690, USA,Department of Medicine, VA Greater Los Angeles Healthcare System, 11301 Wilshire Boulevard, Los Angeles, CA 90073, USA
| | - William Crosson
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, 650 Charles E. Young Drive South, 23-120 CHS, Box 951735, Los Angeles, CA 90095-1735, USA
| | - Milica Momcilovic
- Department of Medicine, Division of Pulmonary and Critical Care, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, 43-229 CHS, Los Angeles, CA 90095-1690, USA
| | - Raymond J. Lim
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, 650 Charles E. Young Drive South, 23-120 CHS, Box 951735, Los Angeles, CA 90095-1735, USA
| | - Stephanie L. Ong
- Department of Medicine, Division of Pulmonary and Critical Care, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, 43-229 CHS, Los Angeles, CA 90095-1690, USA
| | - Zi Ling Huang
- Department of Medicine, Division of Pulmonary and Critical Care, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, 43-229 CHS, Los Angeles, CA 90095-1690, USA
| | - Tianhao Zhang
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, 650 Charles E. Young Drive South, 23-120 CHS, Box 951735, Los Angeles, CA 90095-1735, USA
| | - Jensen Abascal
- Department of Medicine, Division of Pulmonary and Critical Care, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, 43-229 CHS, Los Angeles, CA 90095-1690, USA
| | - Camelia Dumitras
- Department of Medicine, Division of Pulmonary and Critical Care, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, 43-229 CHS, Los Angeles, CA 90095-1690, USA
| | - Zhe Jing
- Department of Medicine, Division of Pulmonary and Critical Care, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, 43-229 CHS, Los Angeles, CA 90095-1690, USA
| | - Stacy J. Park
- Department of Medicine, Division of Pulmonary and Critical Care, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, 43-229 CHS, Los Angeles, CA 90095-1690, USA
| | - Kostyantyn Krysan
- Department of Medicine, Division of Pulmonary and Critical Care, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, 43-229 CHS, Los Angeles, CA 90095-1690, USA
| | - David B. Shackelford
- Department of Medicine, Division of Pulmonary and Critical Care, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, 43-229 CHS, Los Angeles, CA 90095-1690, USA,Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, 650 Charles E. Young Drive South, 23-120 CHS, Box 951735, Los Angeles, CA 90095-1735, USA
| | - Linh M. Tran
- Department of Medicine, Division of Pulmonary and Critical Care, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, 43-229 CHS, Los Angeles, CA 90095-1690, USA
| | - Bin Liu
- Department of Medicine, Division of Pulmonary and Critical Care, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, 43-229 CHS, Los Angeles, CA 90095-1690, USA,Corresponding authors: Bin Liu and Steven M. Dubinett. David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, 43-229 CHS, Los Angeles, CA 90095-1690, USA. Phone: 310-267-2725; ;
| | - Steven M. Dubinett
- Department of Medicine, Division of Pulmonary and Critical Care, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, 43-229 CHS, Los Angeles, CA 90095-1690, USA,Department of Medicine, VA Greater Los Angeles Healthcare System, 11301 Wilshire Boulevard, Los Angeles, CA 90073, USA,Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, 650 Charles E. Young Drive South, 23-120 CHS, Box 951735, Los Angeles, CA 90095-1735, USA,Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, 757 Westwood Plaza, Los Angeles, CA 90095, USA,Jonsson Comprehensive Cancer Center, UCLA, 8-684 Factor Building, Box 951781, Los Angeles, CA 90095-1781, USA,Corresponding authors: Bin Liu and Steven M. Dubinett. David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, 43-229 CHS, Los Angeles, CA 90095-1690, USA. Phone: 310-267-2725; ;
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Mahmoud DE, Kaabachi W, Sassi N, Mokhtar A, Moalla M, Ammar LB, Jemmali S, Rekik S, Tarhouni L, Kallel-Sellami M, Cheour E, Laadhar L. SFRP5 Enhances Wnt5a Induced-Inflammation in Rheumatoid Arthritis Fibroblast-Like Synoviocytes. Front Immunol 2021; 12:663683. [PMID: 34211463 PMCID: PMC8239419 DOI: 10.3389/fimmu.2021.663683] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Accepted: 06/01/2021] [Indexed: 12/24/2022] Open
Abstract
Background Tissue derived fibroblast-like synoviocytes (td-FLS) are key actors in pannus formation and contribute to joint destruction and inflammation during rheumatoid arthritis (RA). Several members of the Wnt family, including Wnt5a, may contribute to RA td-FLS activation and can potentially serve as therapeutic targets. Objective The present work aimed to investigate the expression of Wnt5a signaling elements in RA td-FLS and their potential precursors (fluid derived (fd) FLS and fibrocytes). We also studied the role of Wnt5a in RA td-FLS pro-inflammatory activity and whether the inhibitor SFRP5 could restore Wnt5a-induced synovial dysfunction in vitro. Materials and Methods The levels of Wnt5a, SFRP5, Wnt5a receptors/coreceptors and Wnt5a pro-inflammatory targets were determined in cultured RA td-FLS, fd-FLS and fibrocytes using qPCR under basal conditions. The expression of pro-inflammatory molecules was assessed after RA td-FLS stimulation with Wnt5a and SFRP5 at different time points. Results Our data showed that td-FLS, fd-FLS and fibrocytes from patients with RA expressed similar levels of Wnt5a and a set of Wnt5a receptors/coreceptors. We also demonstrated that Wnt5a stimulated the expression of the pro-inflammatory targets, especially IL1β, IL8 and IL6 in RA td-FLS. Wnt5a-induced inflammation was enhanced in the presence of SFRP5. Furthermore, Wnt5a alone and in conjunction with SFRP5 inhibited the gene expression of TCF4 and the protein levels of the canonical coreceptor LRP5. Conclusion Wnt5a pro-inflammatory effect is not inhibited but enhanced by SFRP5 in RA td-FLS. This research highlights the importance of carefully evaluating changes in Wnt5a response in the presence of SFRP5.
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Affiliation(s)
- Dorra Elhaj Mahmoud
- Immuno-Rheumatology Research Laboratory, Rheumatology Department, La Rabta Hospital, University of Tunis-El Manar, Tunis, Tunisia
| | - Wajih Kaabachi
- Medicine School of Tunis, University of Tunis-El Manar, Tunis, Tunisia
| | - Nadia Sassi
- Immuno-Rheumatology Research Laboratory, Rheumatology Department, La Rabta Hospital, University of Tunis-El Manar, Tunis, Tunisia
| | - Amel Mokhtar
- Immuno-Rheumatology Research Laboratory, Rheumatology Department, La Rabta Hospital, University of Tunis-El Manar, Tunis, Tunisia
| | - Myriam Moalla
- Rheumatology Department, La Rabta Hospital, Tunis, Tunisia
| | | | - Samia Jemmali
- Rheumatology Department, La Rabta Hospital, Tunis, Tunisia
| | - Sonia Rekik
- Rheumatology Department, La Rabta Hospital, Tunis, Tunisia
| | - Lamjed Tarhouni
- Department of Hand and Reconstructive Surgery, Kassab Institute of Traumatic and Orthopedic Surgery, Tunis, Tunisia
| | - Maryam Kallel-Sellami
- Immuno-Rheumatology Research Laboratory, Rheumatology Department, La Rabta Hospital, University of Tunis-El Manar, Tunis, Tunisia
| | - Elhem Cheour
- Immuno-Rheumatology Research Laboratory, Rheumatology Department, La Rabta Hospital, University of Tunis-El Manar, Tunis, Tunisia
| | - Lilia Laadhar
- Immuno-Rheumatology Research Laboratory, Rheumatology Department, La Rabta Hospital, University of Tunis-El Manar, Tunis, Tunisia
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21
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WNT5A inhibition alters the malignant peripheral nerve sheath tumor microenvironment and enhances tumor growth. Oncogene 2021; 40:4229-4241. [PMID: 34079083 PMCID: PMC8217297 DOI: 10.1038/s41388-021-01773-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 12/21/2020] [Accepted: 03/29/2021] [Indexed: 02/05/2023]
Abstract
Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft-tissue sarcomas that cause significant mortality in adults with neurofibromatosis type 1. We compared gene expression of growth factors in normal human nerves to MPNST and normal human Schwann cells to MPNST cell lines. We identified WNT5A as the most significantly upregulated ligand-coding gene and verified its protein expression in MPNST cell lines and tumors. In many contexts WNT5A acts as an oncogene. However, inhibiting WNT5A expression using shRNA did not alter MPNST cell proliferation, invasion, migration, or survival in vitro. Rather, shWNT5A-treated MPNST cells upregulated mRNAs associated with the remodeling of extracellular matrix and with immune cell communication. In addition, these cells secreted increased amounts of the proinflammatory cytokines CXCL1, CCL2, IL6, CXCL8, and ICAM1. Versus controls, shWNT5A-expressing MPNST cells formed larger tumors in vivo. Grafted tumors contained elevated macrophage/stromal cells, larger and more numerous blood vessels, and increased levels of Mmp9, Cxcl13, Lipocalin-1, and Ccl12. In some MPNST settings, these effects were mimicked by targeting the WNT5A receptor ROR2. These data suggest that the non-canonical Wnt ligand WNT5A inhibits MPNST tumor formation by modulating the MPNST microenvironment, so that blocking WNT5A accelerates tumor growth in vivo.
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22
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Khodabandehloo F, Aflatoonian R, Zandieh Z, Rajaei F, Sayahpour FA, Nassiri-Asl M, Baghaban Eslaminejad M. Functional differences of Toll-like receptor 4 in osteogenesis, adipogenesis and chondrogenesis in human bone marrow-derived mesenchymal stem cells. J Cell Mol Med 2021; 25:5138-5149. [PMID: 33939261 PMCID: PMC8178267 DOI: 10.1111/jcmm.16506] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 03/08/2021] [Accepted: 03/12/2021] [Indexed: 12/16/2022] Open
Abstract
Multipotent human bone marrow-derived mesenchymal stem cells (hMSCs) are promising candidates for bone and cartilage regeneration. Toll-like receptor 4 (TLR4) is expressed by hMSCs and is a receptor for both exogenous and endogenous danger signals. TLRs have been shown to possess functional differences based on the species (human or mouse) they are isolated from therefore, the effects of knockdown of TLR4 were evaluated in humans during the differentiation of MSCs into bone, fat and chondrocyte cells in vitro. We investigated the expression profile of TLR4 during the differentiation of hMSCs into three different lineages on days 7, 14 and 21 and assessed the differentiation potential of the cells in the presence of lipopolysaccharide (LPS, as an exogenous agonist) and fibronectin fragment III-1c (FnIII-1c, as an endogenous agonist). TLR4 expression increased following the induction of hMSC differentiation into all three lineages. Alkaline phosphatase activity revealed that FnIII-1c accelerated calcium deposition on day 7, whereas LPS increased calcium deposition on day 14. Chondrogenesis increased in the presence of LPS; however, FnIII-1c acted as a reducer in the late stage. TLR4 silencing led to decreased osteogenesis and increased adipogenesis. Furthermore, Wnt5a expression was inversely related to chondrogenesis during the late stage of differentiation. We suggest that understanding the functionality of TLR4 (in the presence of pathogen or stress signal) during the differentiation of hMSCs into three lineages would be useful for MSC-based treatments.
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Affiliation(s)
| | - Reza Aflatoonian
- Department of Endocrinology and Female Infertility, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
| | - Zahra Zandieh
- Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Farzad Rajaei
- Cellular and Molecular Research Center, Research Institute for Prevention of Non-Communicable Disease, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Forugh-Azam Sayahpour
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Marjan Nassiri-Asl
- Cellular and Molecular Research Center, Research Institute for Prevention of Non-Communicable Disease, Qazvin University of Medical Sciences, Qazvin, Iran.,Department of Pharmacology and Neurobiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohamadreza Baghaban Eslaminejad
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
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23
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The Role of Collagen Triple Helix Repeat-Containing 1 Protein (CTHRC1) in Rheumatoid Arthritis. Int J Mol Sci 2021; 22:ijms22052426. [PMID: 33670905 PMCID: PMC7957534 DOI: 10.3390/ijms22052426] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 01/13/2021] [Accepted: 01/14/2021] [Indexed: 01/15/2023] Open
Abstract
Rheumatoid arthritis (RA) is a chronic autoimmune disease causing inflammation of joints, cartilage destruction and bone erosion. Biomarkers and new drug targets are actively sought and progressed to improve available options for patient treatment. The Collagen Triple Helix Repeat Containing 1 protein (CTHRC1) may have an important role as a biomarker for rheumatoid arthritis, as CTHRC1 protein concentration is significantly elevated in the peripheral blood of rheumatoid arthritis patients compared to osteoarthritis (OA) patients and healthy individuals. CTHRC1 is a secreted glycoprotein that promotes cell migration and has been implicated in arterial tissue-repair processes. Furthermore, high CTHRC1 expression is observed in many types of cancer and is associated with cancer metastasis to the bone and poor patient prognosis. However, the function of CTHRC1 in RA is still largely undefined. The aim of this review is to summarize recent findings on the role of CTHRC1 as a potential biomarker and pathogenic driver of RA progression. We will discuss emerging evidence linking CTHRC1 to the pathogenic behavior of fibroblast-like synoviocytes and to cartilage and bone erosion through modulation of the balance between bone resorption and repair.
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24
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Overexpression of aberrant Wnt5a and its effect on acquisition of malignant phenotypes in adult T-cell leukemia/lymphoma (ATL) cells. Sci Rep 2021; 11:4114. [PMID: 33603066 PMCID: PMC7892546 DOI: 10.1038/s41598-021-83613-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 02/03/2021] [Indexed: 01/31/2023] Open
Abstract
Wnt5a is a ligand of the non-canonical Wnt signaling pathway involved in cell differentiation, motility, and inflammatory response. Adult T-cell leukemia/lymphoma (ATL) is one of the most aggressive T-cell malignancies caused by infection of human T-cell leukemia virus type1 (HTLV-1). Among subtypes of ATL, acute-type ATL cells are particularly resistant to current multidrug chemotherapies and show remarkably high cell-proliferative and invasive phenotypes. Here we show a dramatic increase of WNT5A gene expression in acute-type ATL cells compared with those of indolent-type ATL cells. Treatment with IWP-2 or Wnt5a-specific knockdown significantly suppressed cell growth of ATL-derived T-cell lines. We demonstrated that the overexpression of c-Myb and FoxM1 was responsible for the synergistic activation of the WNT5A promoter. Also, a WNT5A transcript variant without the exon4 (the ΔE4-WNT5A mRNA), encoding ΔC-Wnt5 (1-136aa of 380aa), is overexpressed in acute-type ATL cells. The ΔC-Wnt5a is secreted extracellularly and enhances cellular migration/invasion to a greater extent compared with wildtype (WT)-Wnt5a. Moreover, the ΔC-Wnt5a secretion was not suppressed by IWP-2, indicating that this mutant Wnt5a is secreted via a different pathway from the WT-Wnt5a. Taken together, synergistic overexpression of the ΔC-Wnt5a by c-Myb and FoxM1 may be responsible for the malignant phenotype of acute-type ATL cells.
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25
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Lopez-Bergami P, Barbero G. The emerging role of Wnt5a in the promotion of a pro-inflammatory and immunosuppressive tumor microenvironment. Cancer Metastasis Rev 2021; 39:933-952. [PMID: 32435939 DOI: 10.1007/s10555-020-09878-7] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Wnt5a is the prototypical activator of the non-canonical Wnt pathways, and its overexpression has been implicated in the progression of several tumor types by promoting cell motility, invasion, EMT, and metastasis. Recent evidences have revealed a novel role of Wnt5a in the phosphorylation of the NF-κB subunit p65 and the activation of the NF-κB pathway in cancer cells. In this article, we review the molecular mechanisms and mediators defining a Wnt5a/NF-κB signaling pathway and propose that the aberrant expression of Wnt5a in some tumors drives a Wnt5a/NF-κB/IL-6/STAT3 positive feedback loop that amplifies the effects of Wnt5a. The evidences discussed here suggest that Wnt5a has a double effect on the tumor microenvironment. First, it activates an autocrine ROR1/Akt/p65 pathway that promotes inflammation and chemotaxis of immune cells. Then, Wnt5a activates a TLR/MyD88/p50 pathway exclusively in myelomonocytic cells promoting the synthesis of the anti-inflammatory cytokine IL-10 and a tolerogenic phenotype. As a result of these mechanisms, Wnt5a plays a negative role on immune cell function that contributes to an immunosuppressive tumor microenvironment and would contribute to resistance to immunotherapy. Finally, we summarized the development of different strategies targeting either Wnt5a or the Wnt5a receptor ROR1 that can be helpful for cancer therapy by contributing to generate a more immunostimulatory tumor microenvironment.
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Affiliation(s)
- Pablo Lopez-Bergami
- Centro de Estudios Biomédicos, Básicos, Aplicados y Desarrollo (CEBBAD), Universidad Maimonides, Hidalgo 775, Buenos Aires, Argentina. .,Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina.
| | - Gastón Barbero
- Centro de Estudios Biomédicos, Básicos, Aplicados y Desarrollo (CEBBAD), Universidad Maimonides, Hidalgo 775, Buenos Aires, Argentina.,Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
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26
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Kim S, You D, Jeong Y, Yoon SY, Kim SA, Kim SW, Nam SJ, Lee JE. WNT5A augments cell invasiveness by inducing CXCL8 in HER2-positive breast cancer cells. Cytokine 2020; 135:155213. [DOI: 10.1016/j.cyto.2020.155213] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Revised: 07/13/2020] [Accepted: 07/15/2020] [Indexed: 02/06/2023]
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27
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Recinella L, Orlando G, Ferrante C, Chiavaroli A, Brunetti L, Leone S. Adipokines: New Potential Therapeutic Target for Obesity and Metabolic, Rheumatic, and Cardiovascular Diseases. Front Physiol 2020; 11:578966. [PMID: 33192583 PMCID: PMC7662468 DOI: 10.3389/fphys.2020.578966] [Citation(s) in RCA: 147] [Impact Index Per Article: 29.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 10/14/2020] [Indexed: 12/11/2022] Open
Abstract
Besides its role as an energy storage organ, adipose tissue can be viewed as a dynamic and complex endocrine organ, which produces and secretes several adipokines, including hormones, cytokines, extracellular matrix (ECM) proteins, and growth and vasoactive factors. A wide body of evidence showed that adipokines play a critical role in various biological and physiological functions, among which feeding modulation, inflammatory and immune function, glucose and lipid metabolism, and blood pressure control. The aim of this review is to summarize the effects of several adipokines, including leptin, diponectin, resistin, chemerin, lipocalin-2 (LCN2), vaspin, omentin, follistatin-like 1 (FSTL1), secreted protein acidic and rich in cysteine (SPARC), secreted frizzled-related protein 5 (SFRP5), C1q/TNF-related proteins (CTRPs), family with sequence similarity to 19 member A5 (FAM19A5), wingless-type inducible signaling pathway protein-1 (WISP1), progranulin (PGRN), nesfatin-1 (nesfatin), visfatin/PBEF/NAMPT, apelin, retinol binding protein 4 (RPB4), and plasminogen activator inhibitor-1 (PAI-1) in the regulation of insulin resistance and vascular function, as well as many aspects of inflammation and immunity and their potential role in managing obesity-associated diseases, including metabolic, osteoarticular, and cardiovascular diseases.
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Affiliation(s)
| | | | | | | | - Luigi Brunetti
- Department of Pharmacy, Gabriele d’Annunzio University, Chieti, Italy
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28
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Koopmans T, Hesse L, Nawijn MC, Kumawat K, Menzen MH, Sophie T Bos I, Smits R, Bakker ERM, van den Berge M, Koppelman GH, Guryev V, Gosens R. Smooth-muscle-derived WNT5A augments allergen-induced airway remodelling and Th2 type inflammation. Sci Rep 2020; 10:6754. [PMID: 32317758 PMCID: PMC7174298 DOI: 10.1038/s41598-020-63741-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Accepted: 04/06/2020] [Indexed: 12/21/2022] Open
Abstract
Asthma is a heterogeneous disease characterized by chronic inflammation and structural changes in the airways. The airway smooth muscle (ASM) is responsible for airway narrowing and an important source of inflammatory mediators. We and others have previously shown that WNT5A mRNA and protein expression is higher in the ASM of asthmatics compared to healthy controls. Here, we aimed to characterize the functional role of (smooth muscle-derived) WNT5A in asthma. We generated a tet-ON smooth-muscle-specific WNT5A transgenic mouse model, enabling in vivo characterization of smooth-muscle-derived WNT5A in response to ovalbumin. Smooth muscle specific WNT5A overexpression showed a clear trend towards enhanced actin (α-SMA) expression in the ASM in ovalbumin challenged animals, but had no effect on collagen content. WNT5A overexpression in ASM also significantly enhanced the production of the Th2-cytokines IL4 and IL5 in lung tissue after ovalbumin exposure. In line with this, WNT5A increased mucus production, and enhanced eosinophilic infiltration and serum IgE production in ovalbumin-treated animals. In addition, CD4+ T cells of asthma patients and healthy controls were stimulated with WNT5A and changes in gene transcription assessed by RNA-seq. WNT5A promoted expression of 234 genes in human CD4+ T cells, among which the Th2 cytokine IL31 was among the top 5 upregulated genes. IL31 was also upregulated in response to smooth muscle-specific WNT5A overexpression in the mouse. In conclusion, smooth-muscle derived WNT5A augments Th2 type inflammation and remodelling. Our findings imply a pro-inflammatory role for smooth muscle-derived WNT5A in asthma, resulting in increased airway wall inflammation and remodelling.
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Affiliation(s)
- Tim Koopmans
- Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands.,Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, Groningen, The Netherlands
| | - Laura Hesse
- Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, Groningen, The Netherlands.,University of Groningen, University Medical Center Groningen, Experimental Pulmonology and Inflammation Research, Groningen, The Netherlands
| | - Martijn C Nawijn
- Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, Groningen, The Netherlands.,University of Groningen, University Medical Center Groningen, Experimental Pulmonology and Inflammation Research, Groningen, The Netherlands
| | - Kuldeep Kumawat
- Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands.,Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, Groningen, The Netherlands
| | - Mark H Menzen
- Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands.,Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, Groningen, The Netherlands
| | - I Sophie T Bos
- Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands.,Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, Groningen, The Netherlands
| | - Ron Smits
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Centre, Groningen, The Netherlands
| | - Elvira R M Bakker
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Centre, Groningen, The Netherlands
| | - Maarten van den Berge
- Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, Groningen, The Netherlands.,University of Groningen, University Medical Center Groningen, Department of Pulmonology, Groningen, The Netherlands
| | - Gerard H Koppelman
- Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, Groningen, The Netherlands.,University of Groningen, University Medical Center Groningen, Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children 's Hospital, Groningen, The Netherlands
| | - Victor Guryev
- Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, Groningen, The Netherlands.,European Research Institute for the Biology of Ageing (ERIBA), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Reinoud Gosens
- Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands. .,Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, Groningen, The Netherlands.
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Liu Q, Yang C, Wang S, Shi D, Wei C, Song J, Lin X, Dou R, Bai J, Xiang Z, Huang S, Liu K, Xiong B. Wnt5a-induced M2 polarization of tumor-associated macrophages via IL-10 promotes colorectal cancer progression. Cell Commun Signal 2020; 18:51. [PMID: 32228612 PMCID: PMC7106599 DOI: 10.1186/s12964-020-00557-2] [Citation(s) in RCA: 129] [Impact Index Per Article: 25.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Accepted: 03/23/2020] [Indexed: 01/18/2023] Open
Abstract
Background Tumor-associated macrophages (TAMs) in the tumor microenvironment influence tumor initiation, invasion and metastasis. Several studies have shown that Wnt5a is mainly expressed in the tumor stroma, especially in TAMs. However, whether Wnt5a regulates the polarization and biological function of TAMs in colorectal cancer (CRC) is incompletely understood. Methods Immunofluorescence staining was performed to detect CD68 and Wnt5a expression in colorectal tissues from patients (63 CRC specimens VS 20 normal tissues). RT-qPCR, flow cytometry, ELISA and inhibitors were carried out to explore the role of Wnt5a in the polarization of TAMs. Clone formation and transwell assays were performed to determine the effects of Wnt5a–treated macrophages on tumor proliferation, migration and invasion in vitro. Finally, a xenograft model was applied to confirm the effects of Wnt5a+ TAMs on CRC tumorigenesis. Results We found that high Wnt5a+CD68+/CD68+ TAMs ratio was significantly associated with poor prognosis in CRC patients and Wnt5a+ TAM was an M2-like TAM subtype. Subsequently, we found that Wnt5a induced macrophages to secrete IL-10, which then acted as an autocrine cytokine to induce M2 polarization of these macrophages. IL-10 neutralizing antibody completely reversed the pro-M2 effect of Wnt5a. Mechanistically, the CaKMII-ERK1/2-STAT3 pathway was required for Wnt5a-mediated IL-10 expression in macrophages. Furthermore, Wnt5a-induced M2 macrophages promoted CRC cells proliferation, migration and invasion; knockdown of Wnt5a in TAMs significantly impaired the pro-tumor functions of TAMs. Conclusions Our data indicate that Wnt5a could induce M2 polarization of TAMs by regulating CaKMII-ERK1/2-STAT3 pathway–mediated IL-10 secretion, ultimately promoting tumor growth and metastasis of CRC.
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Affiliation(s)
- Qing Liu
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China.,Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China.,Hubei Key Laboratory of Tumor Biological Behaviors, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China.,Hubei Cancer Clinical Study Center, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China
| | - Chaogang Yang
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China.,Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China.,Hubei Key Laboratory of Tumor Biological Behaviors, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China.,Hubei Cancer Clinical Study Center, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China
| | - Shuyi Wang
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China.,Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China.,Hubei Key Laboratory of Tumor Biological Behaviors, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China.,Hubei Cancer Clinical Study Center, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China
| | - Dongdong Shi
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China.,Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China.,Hubei Key Laboratory of Tumor Biological Behaviors, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China.,Hubei Cancer Clinical Study Center, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China
| | - Chen Wei
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China.,Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China.,Hubei Key Laboratory of Tumor Biological Behaviors, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China.,Hubei Cancer Clinical Study Center, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China
| | - Jialin Song
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China.,Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China.,Hubei Key Laboratory of Tumor Biological Behaviors, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China.,Hubei Cancer Clinical Study Center, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China
| | - Xiaobin Lin
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China.,Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China.,Hubei Key Laboratory of Tumor Biological Behaviors, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China.,Hubei Cancer Clinical Study Center, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China
| | - Rongzhang Dou
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China.,Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China.,Hubei Key Laboratory of Tumor Biological Behaviors, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China.,Hubei Cancer Clinical Study Center, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China
| | - Jian Bai
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China.,Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China.,Hubei Key Laboratory of Tumor Biological Behaviors, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China.,Hubei Cancer Clinical Study Center, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China
| | - Zhenxian Xiang
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China.,Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China.,Hubei Key Laboratory of Tumor Biological Behaviors, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China.,Hubei Cancer Clinical Study Center, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China
| | - Sihao Huang
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China.,Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China.,Hubei Key Laboratory of Tumor Biological Behaviors, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China.,Hubei Cancer Clinical Study Center, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China
| | - Keshu Liu
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China.,Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China.,Hubei Key Laboratory of Tumor Biological Behaviors, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China.,Hubei Cancer Clinical Study Center, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China
| | - Bin Xiong
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China. .,Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China. .,Hubei Key Laboratory of Tumor Biological Behaviors, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China. .,Hubei Cancer Clinical Study Center, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China.
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Herrmann M, Engelke K, Ebert R, Müller-Deubert S, Rudert M, Ziouti F, Jundt F, Felsenberg D, Jakob F. Interactions between Muscle and Bone-Where Physics Meets Biology. Biomolecules 2020; 10:biom10030432. [PMID: 32164381 PMCID: PMC7175139 DOI: 10.3390/biom10030432] [Citation(s) in RCA: 115] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Revised: 02/27/2020] [Accepted: 03/05/2020] [Indexed: 02/06/2023] Open
Abstract
Muscle and bone interact via physical forces and secreted osteokines and myokines. Physical forces are generated through gravity, locomotion, exercise, and external devices. Cells sense mechanical strain via adhesion molecules and translate it into biochemical responses, modulating the basic mechanisms of cellular biology such as lineage commitment, tissue formation, and maturation. This may result in the initiation of bone formation, muscle hypertrophy, and the enhanced production of extracellular matrix constituents, adhesion molecules, and cytoskeletal elements. Bone and muscle mass, resistance to strain, and the stiffness of matrix, cells, and tissues are enhanced, influencing fracture resistance and muscle power. This propagates a dynamic and continuous reciprocity of physicochemical interaction. Secreted growth and differentiation factors are important effectors of mutual interaction. The acute effects of exercise induce the secretion of exosomes with cargo molecules that are capable of mediating the endocrine effects between muscle, bone, and the organism. Long-term changes induce adaptations of the respective tissue secretome that maintain adequate homeostatic conditions. Lessons from unloading, microgravity, and disuse teach us that gratuitous tissue is removed or reorganized while immobility and inflammation trigger muscle and bone marrow fatty infiltration and propagate degenerative diseases such as sarcopenia and osteoporosis. Ongoing research will certainly find new therapeutic targets for prevention and treatment.
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Affiliation(s)
- Marietta Herrmann
- Orthopedic Department, Bernhard-Heine-Center for Locomotion Research, IZKF Research Group Tissue regeneration in musculoskeletal diseases, University Hospital Würzburg, University of Wuerzburg, 97070 Würzburg, Germany;
| | - Klaus Engelke
- Department of Medicine 3, FAU University Erlangen-Nürnberg and Universitätsklinikum Erlangen, 91054 Erlangen, Germany;
| | - Regina Ebert
- Orthopedic Department, Bernhard-Heine-Center for Locomotion Research, University of Würzburg, IGZ, 97076 Würzburg, Germany; (R.E.)
| | - Sigrid Müller-Deubert
- Orthopedic Department, Bernhard-Heine-Center for Locomotion Research, University of Würzburg, IGZ, 97076 Würzburg, Germany; (R.E.)
| | - Maximilian Rudert
- Orthopedic Department, Bernhard-Heine-Center for Locomotion Research, University of Würzburg, 97074 Würzburg, Germany;
| | - Fani Ziouti
- Department of Internal Medicine II, University Hospital Würzburg, 97080 Würzburg, Germany; (F.Z.); (F.J.)
| | - Franziska Jundt
- Department of Internal Medicine II, University Hospital Würzburg, 97080 Würzburg, Germany; (F.Z.); (F.J.)
| | - Dieter Felsenberg
- Privatpraxis für Muskel- und Knochenkrankheiten, 12163 Berlin Germany;
| | - Franz Jakob
- Orthopedic Department, Bernhard-Heine-Center for Locomotion Research, University of Würzburg, IGZ, 97076 Würzburg, Germany; (R.E.)
- Orthopedic Department, Bernhard-Heine-Center for Locomotion Research, University of Würzburg, 97074 Würzburg, Germany;
- Correspondence:
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31
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Asem M, Young AM, Oyama C, Claure De La Zerda A, Liu Y, Yang J, Hilliard TS, Johnson J, Harper EI, Guldner I, Zhang S, Page-Mayberry T, Kaliney WJ, Stack MS. Host Wnt5a Potentiates Microenvironmental Regulation of Ovarian Cancer Metastasis. Cancer Res 2020; 80:1156-1170. [PMID: 31932454 PMCID: PMC8245162 DOI: 10.1158/0008-5472.can-19-1601] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Revised: 08/09/2019] [Accepted: 01/09/2020] [Indexed: 12/19/2022]
Abstract
The noncanonical Wnt ligand Wnt5a is found in high concentrations in ascites of women with ovarian cancer. In this study, we elucidated the role of Wnt5a in ovarian cancer metastasis. Wnt5a promoted ovarian tumor cell adhesion to peritoneal mesothelial cells as well as migration and invasion, leading to colonization of peritoneal explants. Host components of the ovarian tumor microenvironment, notably peritoneal mesothelial cells and visceral adipose, secreted Wnt5a. Conditional knockout of host WNT5A significantly reduced peritoneal metastatic tumor burden. Tumors formed in WNT5A knockout mice had elevated cytotoxic T cells, increased M1 macrophages, and decreased M2 macrophages, indicating that host Wnt5a promotes an immunosuppressive microenvironment. The Src family kinase Fgr was identified as a downstream effector of Wnt5a. These results highlight a previously unreported role for host-expressed Wnt5a in ovarian cancer metastasis and suggest Fgr as a novel target for inhibition of ovarian cancer metastatic progression.Significance: This study establishes host-derived Wnt5a, expressed by peritoneal mesothelial cells and adipocytes, as a primary regulator of ovarian cancer intraperitoneal metastatic dissemination and identifies Fgr kinase as novel target for inhibition of metastasis.
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Affiliation(s)
- Marwa Asem
- Integrated Biomedical Sciences Program, University of Notre Dame, South Bend, Indiana
- Department of Chemistry and Biochemistry, University of Notre Dame, South Bend, Indiana
- Harper Cancer Research Institute, University of Notre Dame, South Bend, Indiana
| | - Allison M Young
- Harper Cancer Research Institute, University of Notre Dame, South Bend, Indiana
| | - Carlysa Oyama
- Harper Cancer Research Institute, University of Notre Dame, South Bend, Indiana
| | | | - Yueying Liu
- Department of Chemistry and Biochemistry, University of Notre Dame, South Bend, Indiana
- Harper Cancer Research Institute, University of Notre Dame, South Bend, Indiana
| | - Jing Yang
- Department of Chemistry and Biochemistry, University of Notre Dame, South Bend, Indiana
- Harper Cancer Research Institute, University of Notre Dame, South Bend, Indiana
| | - Tyvette S Hilliard
- Department of Chemistry and Biochemistry, University of Notre Dame, South Bend, Indiana
- Harper Cancer Research Institute, University of Notre Dame, South Bend, Indiana
| | - Jeffery Johnson
- Department of Chemistry and Biochemistry, University of Notre Dame, South Bend, Indiana
- Harper Cancer Research Institute, University of Notre Dame, South Bend, Indiana
| | - Elizabeth I Harper
- Department of Chemistry and Biochemistry, University of Notre Dame, South Bend, Indiana
- Harper Cancer Research Institute, University of Notre Dame, South Bend, Indiana
| | - Ian Guldner
- Harper Cancer Research Institute, University of Notre Dame, South Bend, Indiana
- Department of Biological Sciences, University of Notre Dame; South Bend, Indiana
| | - Siyuan Zhang
- Harper Cancer Research Institute, University of Notre Dame, South Bend, Indiana
- Department of Biological Sciences, University of Notre Dame; South Bend, Indiana
| | - Toni Page-Mayberry
- Harper Cancer Research Institute, University of Notre Dame, South Bend, Indiana
| | - William J Kaliney
- Harper Cancer Research Institute, University of Notre Dame, South Bend, Indiana
| | - M Sharon Stack
- Integrated Biomedical Sciences Program, University of Notre Dame, South Bend, Indiana.
- Department of Chemistry and Biochemistry, University of Notre Dame, South Bend, Indiana
- Harper Cancer Research Institute, University of Notre Dame, South Bend, Indiana
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Liu Q, Song J, Pan Y, Shi D, Yang C, Wang S, Xiong B. Wnt5a/CaMKII/ERK/CCL2 axis is required for tumor-associated macrophages to promote colorectal cancer progression. Int J Biol Sci 2020; 16:1023-1034. [PMID: 32140070 PMCID: PMC7053330 DOI: 10.7150/ijbs.40535] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2019] [Accepted: 12/30/2019] [Indexed: 12/12/2022] Open
Abstract
Tumor-associated macrophages (TAMs) are closely correlated with tumor occurrence, invasion, and metastasis. However, factors affecting the biological functions of TAMs in colorectal cancer (CRC) are incompletely understood. Here, we found that Wnt5a was mainly expressed on TAMs of tumor stroma but not on CRC cells. Subsequently, we found that Wnt5a+ TAMs facilitated tumor cell proliferation and migration, and recruited macrophages infiltration. Furthermore, Wnt5a knockdown impaired the pro-tumor roles of TAMs in vivo and in vitro. Mechanistically, the cancer-promoting roles of Wnt5a in TAMs depended on CaMKII-ERK pathway-mediated CCL2 secretion. Our data reveal the crucial role played by TAM-expressed Wnt5a in CRC tumorigenesis through paracrine secretion of CCL2. We first report the connection between Wnt5a/CaMKII/ERK/CCL2 axis and biological functions of TAMs in tumor microenvironment, indicating that Wnt5a may be a novel therapeutic target for CRC.
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Affiliation(s)
- Qing Liu
- Department of Gastrointestinal Surgery & Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.,Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan 430071, China.,Hubei Cancer Clinical Study Center, Wuhan 430071, China
| | - Jialin Song
- Department of Gastrointestinal Surgery & Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.,Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan 430071, China.,Hubei Cancer Clinical Study Center, Wuhan 430071, China
| | - Yue Pan
- Department of Intensive Care Unit, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Dongdong Shi
- Department of Gastrointestinal Surgery & Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.,Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan 430071, China.,Hubei Cancer Clinical Study Center, Wuhan 430071, China
| | - Chaogang Yang
- Department of Gastrointestinal Surgery & Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.,Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan 430071, China.,Hubei Cancer Clinical Study Center, Wuhan 430071, China
| | - Shuyi Wang
- Department of Gastrointestinal Surgery & Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.,Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan 430071, China.,Hubei Cancer Clinical Study Center, Wuhan 430071, China
| | - Bin Xiong
- Department of Gastrointestinal Surgery & Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.,Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan 430071, China.,Hubei Cancer Clinical Study Center, Wuhan 430071, China
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33
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Wnt signaling mediates TLR pathway and promote unrestrained adipogenesis and metaflammation: Therapeutic targets for obesity and type 2 diabetes. Pharmacol Res 2019; 152:104602. [PMID: 31846761 DOI: 10.1016/j.phrs.2019.104602] [Citation(s) in RCA: 69] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2019] [Revised: 11/17/2019] [Accepted: 12/13/2019] [Indexed: 12/11/2022]
Abstract
Diabesity is the combination of type 2 diabetes and obesity characterized by chronic low-grade inflammation. The Wnt signaling act as an evolutionary pathway playing crucial role in regulating cellular homeostasis and energy balance from hypothalamus to metabolic organs. Aberrant activity of certain appendages in the canonical and non-canonical Wnt system deregulates metabolism and leads to adipose tissue expansion, this key event initiates metabolic stress causing metaflammation and obesity. Metaflammation induced obesity initiates abnormal development of adipocytes mediating through the non-canonical Wnt signaling inhibition of canonical Wnt pathway to fan the flames of adipogenesis. Moreover, activation of toll like receptor (TLR)-4 signaling in metabolic stress invites immune cells to release pro-inflammatory cytokines for recruitment of macrophages in adipose tissues, further causes polarization of macrophages into M1(classically activated) and M2 (alternatively activated) subtypes. These events end with chronic low-grade inflammation which interferes with insulin signaling in metabolic tissues to develop type 2 diabetes. However, there is a dearth in understanding the exact mechanism of Wnt-TLR axis during diabesity. This review dissects the molecular facets of Wnt and TLRs that modulates cellular components during diabesity and provides current progress, challenges and alternative therapeutic strategies at preclinical and clinical level.
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34
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Ljungberg JK, Kling JC, Tran TT, Blumenthal A. Functions of the WNT Signaling Network in Shaping Host Responses to Infection. Front Immunol 2019; 10:2521. [PMID: 31781093 PMCID: PMC6857519 DOI: 10.3389/fimmu.2019.02521] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Accepted: 10/10/2019] [Indexed: 12/15/2022] Open
Abstract
It is well-established that aberrant WNT expression and signaling is associated with developmental defects, malignant transformation and carcinogenesis. More recently, WNT ligands have emerged as integral components of host responses to infection but their functions in the context of immune responses are incompletely understood. Roles in the modulation of inflammatory cytokine production, host cell intrinsic innate defense mechanisms, as well as the bridging of innate and adaptive immunity have been described. To what degree WNT responses are defined by the nature of the invading pathogen or are specific for subsets of host cells is currently not well-understood. Here we provide an overview of WNT responses during infection with phylogenetically diverse pathogens and highlight functions of WNT ligands in the host defense against infection. Detailed understanding of how the WNT network orchestrates immune cell functions will not only improve our understanding of the fundamental principles underlying complex immune response, but also help identify therapeutic opportunities or potential risks associated with the pharmacological targeting of the WNT network, as currently pursued for novel therapeutics in cancer and bone disorders.
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Affiliation(s)
- Johanna K Ljungberg
- The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, QLD, Australia
| | - Jessica C Kling
- The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, QLD, Australia
| | - Thao Thanh Tran
- The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, QLD, Australia
| | - Antje Blumenthal
- The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, QLD, Australia
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35
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The Regulation of Bone Metabolism and Disorders by Wnt Signaling. Int J Mol Sci 2019; 20:ijms20225525. [PMID: 31698687 PMCID: PMC6888566 DOI: 10.3390/ijms20225525] [Citation(s) in RCA: 234] [Impact Index Per Article: 39.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Revised: 11/03/2019] [Accepted: 11/04/2019] [Indexed: 12/21/2022] Open
Abstract
Wnt, a secreted glycoprotein, has an approximate molecular weight of 40 kDa, and it is a cytokine involved in various biological phenomena including ontogeny, morphogenesis, carcinogenesis, and maintenance of stem cells. The Wnt signaling pathway can be classified into two main pathways: canonical and non-canonical. Of these, the canonical Wnt signaling pathway promotes osteogenesis. Sclerostin produced by osteocytes is an inhibitor of this pathway, thereby inhibiting osteogenesis. Recently, osteoporosis treatment using an anti-sclerostin therapy has been introduced. In this review, the basics of Wnt signaling, its role in bone metabolism and its involvement in skeletal disorders have been covered. Furthermore, the clinical significance and future scopes of Wnt signaling in osteoporosis, osteoarthritis, rheumatoid arthritis and neoplasia are discussed.
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36
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An Autocrine Wnt5a Loop Promotes NF-κB Pathway Activation and Cytokine/Chemokine Secretion in Melanoma. Cells 2019; 8:cells8091060. [PMID: 31510045 PMCID: PMC6770184 DOI: 10.3390/cells8091060] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Revised: 08/29/2019] [Accepted: 09/05/2019] [Indexed: 12/19/2022] Open
Abstract
Wnt5a signaling has been implicated in the progression of cancer by regulating multiple cellular processes, largely migration and invasion, epithelial-mesenchymal transition (EMT), and metastasis. Since Wnt5a signaling has also been involved in inflammatory processes in infectious and inflammatory diseases, we addressed the role of Wnt5a in regulating NF-κB, a pivotal mediator of inflammatory responses, in the context of cancer. The treatment of melanoma cells with Wnt5a induced phosphorylation of the NF-κB subunit p65 as well as IKK phosphorylation and IκB degradation. By using cDNA overexpression, RNA interference, and dominant negative mutants we determined that ROR1, Dvl2, and Akt (from the Wnt5a pathway) and TRAF2 and RIP (from the NF-κB pathway) are required for the Wnt5a/NF-κB crosstalk. Wnt5a also induced p65 nuclear translocation and increased NF-κB activity as evidenced by reporter assays and a NF-κB-specific upregulation of RelB, Bcl-2, and Cyclin D1. Further, stimulation of melanoma cells with Wnt5a increased the secretion of cytokines and chemokines, including IL-6, IL-8, IL-11, and IL-6 soluble receptor, MCP-1, and TNF soluble receptor I. The inhibition of endogenous Wnt5a demonstrated that an autocrine Wnt5a loop is a major regulator of the NF-κB pathway in melanoma. Taken together, these results indicate that Wnt5a activates the NF-κB pathway and has an immunomodulatory effect on melanoma through the secretion of cytokines and chemokines.
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37
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Tian F, Mauro TM, Li Z. The pathological role of Wnt5a in psoriasis and psoriatic arthritis. J Cell Mol Med 2019; 23:5876-5883. [PMID: 31313518 PMCID: PMC6714168 DOI: 10.1111/jcmm.14531] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Revised: 05/30/2019] [Accepted: 06/13/2019] [Indexed: 12/19/2022] Open
Abstract
Psoriasis (PsO) is a chronic inflammatory skin disease with both local and systemic components. PsO‐associated arthritis, known as psoriatic arthritis (PsA), develops in approximately 13%‐25% of PsO patients. Various factors associated with both PsO and PsA indicate that these conditions are part of a single disease. Identification of novel targets for the development of drugs to treat both PsO and PsA is desirable to provide more patient‐friendly treatment regimens. Such targets will likely represent ‘common checkpoints’ of inflammation, for example key components or transduction cascades of the signalling pathways involved. Emerging evidence supports involvement of the non‐canonical Wnt signalling pathways in the development of both PsO and PsA, especially the Wnt5a‐activated signalling cascades. These, together with interlinked factors, are crucial in the interactions among keratinocytes, immune cells and inflammatory factors in PsO, as well as among chondrocytes, osteoblasts and osteoclasts that trigger both subchondral bone remodelling and cartilage catabolism in PsA. This review focuses on the pathological role of Wnt5a signalling and its interaction with other interlinked pathways in both PsO and PsA, and also on the main challenges for future research, particularly with respect to molecules targeting Wnt signalling pathways for the treatment of PsO and PsA.
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Affiliation(s)
- Faming Tian
- Medical Research Center, North China University of Science and Technology, Tangshan, China
| | - Theodora M Mauro
- Dermatology Services, Veterans Affair Medical Center and University of California-San Francisco, San Francisco, CA, USA
| | - Zhengxiao Li
- Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
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38
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Yu T, Dong D, Guan J, Sun J, Guo M, Wang Q. Alprostadil attenuates LPS-induced cardiomyocyte injury by inhibiting the Wnt5a/JNK/NF-κB pathway. Herz 2019; 45:130-138. [PMID: 31312872 PMCID: PMC7721679 DOI: 10.1007/s00059-019-4837-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Revised: 06/19/2019] [Accepted: 06/21/2019] [Indexed: 12/24/2022]
Abstract
Background Clinical research has demonstrated that alprostadil has an anti-inflammatory effect; however, to date, its molecular mechanisms remain unclear. This study aimed to examine the anti-inflammatory activity and related mechanisms of alprostadil in lipopolysaccharide (LPS)-treated H9c2 cells. Methods Cell morphology was observed under an inverted light microscope, while cell viability was assessed with the 3‑(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) assay. Enzyme-linked immunosorbent assays (ELISA) were conducted to study biochemical indicators of cellular damage, such as released lactate dehydrase (LDH) and troponin, and inflammatory cytokine levels including interleukin-1β (IL-1β), IL-6, IL-17, and tumor necrosis factor-α (TNF-α). The mRNA expression levels of Wnt5a, c‑jun N‑terminal kinase (JNK), and nuclear factor kappa B (NF-κB) were further investigated by real-time quantitative polymerase chain reaction (RT-PCR). The effects of alprostadil on the Wnt5a/JNK/NF-κB pathway in H9c2 cells was examined by Western blotting. Results Alprostadil increased the cell viability of LPS-stimulated H9c2 cells, reduced LDH and troponin production, and attenuated IL-1β, IL-6, IL-17, and TNF-α secretion. Moreover, alprostadil reduced the mRNA expression of Wnt5a, JNK, and NF-κB and decreased the expression of Wnt5a, NF-κB, and the ratio of p‑JNK/JNK in H9c2 cells treated with LPS. The siWnt5a or JNK inhibitor SP600125 significantly augmented the inhibitory effects of alprostadil on the Wnt5a/JNK/NF-κB pathway. Conclusion Our results show that alprostadil has anti-inflammatory effects and could attenuate LPS-induced injury in H9c2 cardiomyocytes via the Wnt5a/JNK/NF-κB pathway.
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Affiliation(s)
- T Yu
- Department of Emergency, Affiliated Hospital of Qingdao University, Jiangsu Road No. 16, Qingdao, Shandong, China
| | - D Dong
- Department of Cardiology, No. 971 Hospital of People's Liberation Army, Minjiang Road No. 22, Qingdao, Shandong, China
| | - J Guan
- Department of Emergency, Affiliated Hospital of Qingdao University, Jiangsu Road No. 16, Qingdao, Shandong, China
| | - J Sun
- Department of Emergency, Affiliated Hospital of Qingdao University, Jiangsu Road No. 16, Qingdao, Shandong, China
| | - M Guo
- Department of Emergency, Affiliated Hospital of Qingdao University, Jiangsu Road No. 16, Qingdao, Shandong, China
| | - Q Wang
- Department of Emergency, Affiliated Hospital of Qingdao University, Jiangsu Road No. 16, Qingdao, Shandong, China.
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Balaian E, Weidner H, Wobus M, Baschant U, Jacobi A, Mies A, Bornhäuser M, Guck J, Hofbauer LC, Rauner M, Platzbecker U. Effects of rigosertib on the osteo-hematopoietic niche in myelodysplastic syndromes. Ann Hematol 2019; 98:2063-2072. [PMID: 31312928 DOI: 10.1007/s00277-019-03756-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Accepted: 07/08/2019] [Indexed: 12/12/2022]
Abstract
Rigosertib is a novel multi-kinase inhibitor, which has clinical activity towards leukemic progenitor cells of patients with high-risk myelodysplastic syndromes (MDS) after failure or progression on hypomethylating agents. Since the bone marrow microenvironment plays an important role in MDS pathogenesis, we investigated the impact of rigosertib on cellular compartments within the osteo-hematopoietic niche. Healthy C57BL/6J mice treated with rigosertib for 3 weeks showed a mild suppression of hematopoiesis (hemoglobin and red blood cells, both - 16%, p < 0.01; white blood cells, - 34%, p < 0.05; platelets, - 38%, p < 0.05), whereas there was no difference in the number of hematopoietic stem cells in the bone marrow. Trabecular bone mass of the spine was reduced by rigosertib (- 16%, p = 0.05). This was accompanied by a lower trabecular number and thickness (- 6% and - 10%, respectively, p < 0.05), partly explained by the increase in osteoclast number and surface (p < 0.01). Milder effects of rigosertib on bone mass were detected in an MDS mouse model system (NHD13). However, rigosertib did not further aggravate MDS-associated cytopenia in NHD13 mice. Finally, we tested the effects of rigosertib on human mesenchymal stromal cells (MSC) in vitro and demonstrated reduced cell viability at nanomolar concentrations. Deterioration of the hematopoietic supportive capacity of MDS-MSC after rigosertib pretreatment demonstrated by decreased number of colony-forming units, especially in the monocytic lineage, further supports the idea of disturbed crosstalk within the osteo-hematopoietic niche mediated by rigosertib. Thus, rigosertib exerts inhibitory effects on the stromal components of the osteo-hematopoietic niche which may explain the dissociation between anti-leukemic activity and the absence of hematological improvement.
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Affiliation(s)
- Ekaterina Balaian
- Medical Clinic I, University Hospital Carl Gustav Carus Dresden, Dresden, Germany
| | - Heike Weidner
- Medical Clinic III, University Hospital Carl Gustav Carus Dresden, Dresden, Germany.,Center for Healthy Aging, University Hospital Carl Gustav Carus Dresden, Dresden, Germany
| | - Manja Wobus
- Medical Clinic I, University Hospital Carl Gustav Carus Dresden, Dresden, Germany
| | - Ulrike Baschant
- Medical Clinic III, University Hospital Carl Gustav Carus Dresden, Dresden, Germany.,Center for Healthy Aging, University Hospital Carl Gustav Carus Dresden, Dresden, Germany
| | - Angela Jacobi
- Biotechnology Center, Center for Molecular and Cellular Bioengineering, TU Dresden, Dresden, Germany
| | - Anna Mies
- Medical Clinic I, University Hospital Carl Gustav Carus Dresden, Dresden, Germany
| | - Martin Bornhäuser
- Medical Clinic I, University Hospital Carl Gustav Carus Dresden, Dresden, Germany.,German Cancer Consortium (DKTK), Partner Site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany.,National Center for Tumor Diseases (NCT Partner Site Dresden), DKFZ, Heidelberg, Germany
| | - Jochen Guck
- Biotechnology Center, Center for Molecular and Cellular Bioengineering, TU Dresden, Dresden, Germany
| | - Lorenz C Hofbauer
- Medical Clinic III, University Hospital Carl Gustav Carus Dresden, Dresden, Germany.,Center for Healthy Aging, University Hospital Carl Gustav Carus Dresden, Dresden, Germany.,German Cancer Consortium (DKTK), Partner Site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Martina Rauner
- Medical Clinic III, University Hospital Carl Gustav Carus Dresden, Dresden, Germany.,Center for Healthy Aging, University Hospital Carl Gustav Carus Dresden, Dresden, Germany
| | - Uwe Platzbecker
- Medical Clinic and Policlinic 1, Hematology and Cellular Therapy, Leipzig University Hospital, Liebigstraße 22, 04103, Leipzig, Germany. .,German MDS Study Group (G-MDS), Leipzig, Germany. .,European Myelodysplastic Syndromes Cooperative Group (EMSCO group), .
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40
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Gao Y, Wen Q, Hu S, Zhou X, Xiong W, Du X, Zhang L, Fu Y, Yang J, Zhou C, Zhang Z, Li Y, Liu H, Huang Y, Ma L. IL-36γ Promotes Killing of Mycobacterium tuberculosis by Macrophages via WNT5A-Induced Noncanonical WNT Signaling. THE JOURNAL OF IMMUNOLOGY 2019; 203:922-935. [PMID: 31235551 DOI: 10.4049/jimmunol.1900169] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Accepted: 06/07/2019] [Indexed: 12/12/2022]
Abstract
Mycobacterium tuberculosis, which primarily infects mononuclear phagocytes, remains the leading bacterial cause of enormous morbidity and mortality because of bacterial infections in humans throughout the world. The IL-1 family of cytokines is critical for host resistance to M. tuberculosis As a newly discovered subgroup of the IL-1 family, although IL-36 cytokines have been proven to play roles in protection against M. tuberculosis infection, the antibacterial mechanisms are poorly understood. In this study, we demonstrated that IL-36γ conferred to human monocyte-derived macrophages bacterial resistance through activation of autophagy as well as induction of WNT5A, a reported downstream effector of IL-1 involved in several inflammatory diseases. Further studies showed that WNT5A could enhance autophagy of monocyte-derived macrophages by inducing cyclooxygenase-2 (COX-2) expression and in turn decrease phosphorylation of AKT/mTOR via noncanonical WNT signaling. Consistently, the underlying molecular mechanisms of IL-36γ function are also mediated by the COX-2/AKT/mTOR signaling axis. Altogether, our findings reveal a novel activity for IL-36γ as an inducer of autophagy, which represents a critical inflammatory cytokine that control the outcome of M. tuberculosis infection in human macrophages.
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Affiliation(s)
- Yuchi Gao
- Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China
| | - Qian Wen
- Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China
| | - Shengfeng Hu
- Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China
| | - Xinying Zhou
- Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China
| | - Wenjing Xiong
- Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China
| | - Xialin Du
- Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China
| | - Lijie Zhang
- Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China
| | - Yuling Fu
- Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China
| | - Jiahui Yang
- Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China
| | - Chaoying Zhou
- Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China
| | - Zelin Zhang
- Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China
| | - Yanfen Li
- Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China
| | - Honglin Liu
- Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China
| | - Yulan Huang
- Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China
| | - Li Ma
- Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China
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Haftcheshmeh SM, Mohammadi A, Soltani A, Momtazi-Borojeni AA, Sattari M. Evaluation of STAT1 and Wnt5a gene expression in gingival tissues of patients with periodontal disease. J Cell Biochem 2019; 120:1827-1834. [PMID: 30324689 DOI: 10.1002/jcb.27487] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2018] [Accepted: 07/20/2018] [Indexed: 01/24/2023]
Abstract
Periodontal disease is a common chronic inflammatory disease of the oral cavity. This disease occurs as a consequence of uncontrolled inflammatory immune responses against periodontopathic bacteria. Several studies have documented the proinflammatory roles of the Signal Transducer and Activator of Transcription 1 (STAT1) and Wnt5a in inflammatory diseases. However, there has been no detailed investigation of STAT1 and Wnt5a genes expression in periodontal disease. So, we aimed to evaluate the expressions of STAT1 and Wnt5a in patients with chronic and aggressive periodontitis and determine their correlation with clinical parameters. Three groups of subjects were enrolled including control (20 healthy individuals), chronic (25 patients), and aggressive periodontitis patients (25 patients). The expressions of STAT1 and Wnt5a were evaluated in gingival tissue samples using a Real-time polymerase chain reactions assay. The expressions of STAT1 and Wnt5a were significantly upregulated in chronic and aggressive periodontitis compared with the healthy control. We also found that the expressions of STAT1 and Wnt5a increased in aggressive periodontitis compared with chronic periodontitis. In addition, there was the linear relationship between the expression of STAT1 and Wnt5a and the clinical parameters, including clinical attachment loss and periodontal pocket depth. A linear relationship between the expressions of Wnt5a and the clinical parameters was also identified. Taken together, our findings highlight the roles of STAT1 and Wnt5a in the pathogenesis of the periodontal inflammation, suggesting these molecules as valuable therapeutic targets.
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Affiliation(s)
- Saeed Mohammadian Haftcheshmeh
- Department of Medical immunology, Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Medical Immunology, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Asadollah Mohammadi
- Cellular & Molecular Research Center, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran.,Department of Medical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Arash Soltani
- Department of Medical Biotechnology, Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amir Abbas Momtazi-Borojeni
- Nanotechnology Research Center, Bu-Ali Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mandana Sattari
- Department of Medical Immunology, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Dental Research Center, Research Institute of Dental Sciences, School of Dentistry, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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42
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Harun NH, Froemming GRA, Nawawi HM, Muid SA. Inflammation and Vascular Calcification Causing Effects of Oxidized HDL are Attenuated by Adiponectin in Human Vascular Smooth Muscle Cells. INTERNATIONAL JOURNAL OF MOLECULAR AND CELLULAR MEDICINE 2019; 8:39-55. [PMID: 32195204 PMCID: PMC7073262 DOI: 10.22088/ijmcm.bums.8.1.39] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Accepted: 06/15/2019] [Indexed: 11/17/2022]
Abstract
The role of oxidized high- density lipoprotein (oxHDL) and the protective effects of adiponectin in terms of vascular calcification is not well-established. This study was conducted to investigate the effects of oxHDL with regard to inflammation and vascular calcification and to determine the protective role of adiponectin in attenuating the detrimental effects of oxHDL. Cell viability, mineralization, and calcification assays were conducted to optimize the concentration of oxHDL. Then, human vascular smooth muscle cells (HAoVSMCs) were incubated with β-glycerophosphate, HDL, oxHDL, adiponectin, or the combination of oxHDL with adiponectin for 24 h. Protein expression of IL-6, TNF-α, osterix, RUNX2, ALP, type 1 collagen, osteopontin, osteocalcin, WNT-5a, NF-ĸβ(p65), cAMP and STAT-3 were measured by ELISA kits. OxHDL induced vascular calcification by promoting the formation of mineralization nodules and calcium deposits in HAoVSMCs. This was accompanied by an increased secretion of IL-6, osterix, WNT-5a and NF-ĸβ (p65). Interestingly, these detrimental effects of oxHDL were suppressed by adiponectin. Besides, incubation of adiponectin alone on HAoVSMCs showed a reduction of inflammatory cytokines, osteoblastic markers (RUNX2, osterix and osteopontin), WNT-5a and NF-ĸβ (p65). This study exhibits the ability of oxHDL in inducing inflammation and vascular calcification and these detrimental effects of oxHDL can be attenuated by adiponectin.
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Affiliation(s)
- Noor Hanisa Harun
- Faculty of Medicine, Universiti Teknologi MARA, Cawangan Selangor, Sungai Buloh Campus, Selangor, Malaysia
| | | | - Hapizah Md Nawawi
- Faculty of Medicine, Universiti Teknologi MARA, Cawangan Selangor, Sungai Buloh Campus, Selangor, Malaysia.,Institute of Pathology, Laboratory and Forensic Medicine (I-PPerForM), Universiti Teknologi MARA, Sungai Buloh Campus, Selangor, Malaysia
| | - Suhaila Abd Muid
- Faculty of Medicine, Universiti Teknologi MARA, Cawangan Selangor, Sungai Buloh Campus, Selangor, Malaysia.,Institute of Pathology, Laboratory and Forensic Medicine (I-PPerForM), Universiti Teknologi MARA, Sungai Buloh Campus, Selangor, Malaysia
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Hafen B, Wiesner S, Schlegelmilch K, Keller A, Seefried L, Ebert R, Walles H, Jakob F, Schütze N. Physical contact between mesenchymal stem cells and endothelial precursors induces distinct signatures with relevance to the very early phase of regeneration. J Cell Biochem 2018; 119:9122-9140. [PMID: 30105832 DOI: 10.1002/jcb.27175] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2017] [Accepted: 05/14/2018] [Indexed: 12/27/2022]
Abstract
Multipotent adult stem cells/precursor cells, especially of the mesenchymal and endothelial lineage, may have great potential for bone tissue engineering. Although their potential is highly recognized, not much is known about the underlying molecular mechanisms that initiate the regeneration process, connect osteogenesis, and angiogenesis and, finally, orchestrate renewal of bone tissue. Our study addressed these questions by generating two in vitro cell culture models to examine the changes in the global gene expression patterns of endothelial precursor cells and mesenchymal stem cells after 24 hours of either humoral (conditioned medium) or direct cell-cell interaction (co-culture). Endothelial precursor cells were isolated from human buffy coat and mesenchymal stem cells from the bone marrow of the femoral head. The comparison of the treated and control cells by microarray analyses revealed in total more than 1500 regulated genes, which were analyzed for their affiliation to angiogenesis and osteogenesis. Expression array analyses at the RNA and protein level revealed data with respect to regulated genes, pathways and targets that may represent a valid basis for further dissection of the systems biology of regeneration processes. It may also be helpful for the reconstitution of the natural composition of a regenerative microenvironment when targeting tissue regeneration both in vitro and in situ.
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Affiliation(s)
- Bettina Hafen
- Orthopedic Clinic, Orthopedic Center for Musculoskeletal Research, University of Würzburg, Germany.,Immundiagnostik AG, Bensheim, Germany
| | - Susanne Wiesner
- Orthopedic Clinic, Orthopedic Center for Musculoskeletal Research, University of Würzburg, Germany
| | - Katrin Schlegelmilch
- Department for Functional Materials in Medicine and Dentistry, University of Würzburg, Germany
| | - Alexander Keller
- DNA Analytics Core Facility, Department of Animal Ecology and Tropical Biology, Biocenter, University of Würzburg, Germany
| | - Lothar Seefried
- Orthopedic Clinic, Orthopedic Center for Musculoskeletal Research, University of Würzburg, Germany
| | - Regina Ebert
- Orthopedic Clinic, Orthopedic Center for Musculoskeletal Research, University of Würzburg, Germany
| | - Heike Walles
- Department of Tissue Engineering and Regenerative Medicine (TERM), University Hospital Würzburg, Germany.,Translational Center Würzburg "Regenerative therapies in oncology and musculoskeletal disease," Würzburg branch of the Fraunhofer-Institute Interfacial Engineering and Biotechnology, IGB, Germany
| | - Franz Jakob
- Orthopedic Clinic, Orthopedic Center for Musculoskeletal Research, University of Würzburg, Germany
| | - Norbert Schütze
- Orthopedic Clinic, Orthopedic Center for Musculoskeletal Research, University of Würzburg, Germany
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Feller D, Kun J, Ruzsics I, Rapp J, Sarosi V, Kvell K, Helyes Z, Pongracz JE. Cigarette Smoke-Induced Pulmonary Inflammation Becomes Systemic by Circulating Extracellular Vesicles Containing Wnt5a and Inflammatory Cytokines. Front Immunol 2018; 9:1724. [PMID: 30090106 PMCID: PMC6068321 DOI: 10.3389/fimmu.2018.01724] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2018] [Accepted: 07/12/2018] [Indexed: 01/09/2023] Open
Abstract
Chronic obstructive pulmonary disease (COPD) is a devastating, irreversible pathology affecting millions of people worldwide. Clinical studies show that currently available therapies are insufficient, have no or little effect on elevated comorbidities and on systemic inflammation. To develop alternative therapeutic options, a better understanding of the molecular background of COPD is essential. In the present study, we show that non-canonical and pro-inflammatory Wnt5a is up-regulated by cigarette smoking with parallel up-regulation of pro-inflammatory cytokines in both mouse and human model systems. Wnt5a is not only a pro-inflammatory Wnt ligand but can also inhibit the anti-inflammatory peroxisome proliferator-activated receptor gamma transcription and affect M1/M2 macrophage polarization. Both Wnt5a and pro-inflammatory cytokines can be transported in lipid bilayer sealed extracellular vesicles that reach and deliver their contents to every organ measured in the blood of COPD patients, therefore, demonstrating a potential mechanism for the systemic nature of this crippling disease.
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Affiliation(s)
- Diana Feller
- Department of Pharmaceutical Biotechnology, School of Pharmacy, University of Pecs, Pecs, Hungary.,Department of Pharmacology and Pharmacotherapy, Medical School, University of Pecs, Pecs, Hungary.,Szentagothai Research Center, University of Pecs, Pecs, Hungary
| | - Jozsef Kun
- Department of Pharmacology and Pharmacotherapy, Medical School, University of Pecs, Pecs, Hungary.,Szentagothai Research Center, University of Pecs, Pecs, Hungary
| | - Istvan Ruzsics
- Department of Internal Medicine, Clinical Centre and Medical School, University of Pecs, Pecs, Hungary
| | - Judit Rapp
- Department of Pharmaceutical Biotechnology, School of Pharmacy, University of Pecs, Pecs, Hungary.,Szentagothai Research Center, University of Pecs, Pecs, Hungary
| | - Veronika Sarosi
- Department of Internal Medicine, Clinical Centre and Medical School, University of Pecs, Pecs, Hungary
| | - Krisztian Kvell
- Department of Pharmaceutical Biotechnology, School of Pharmacy, University of Pecs, Pecs, Hungary.,Szentagothai Research Center, University of Pecs, Pecs, Hungary
| | - Zsuzsanna Helyes
- Department of Pharmacology and Pharmacotherapy, Medical School, University of Pecs, Pecs, Hungary.,Szentagothai Research Center, University of Pecs, Pecs, Hungary
| | - Judit E Pongracz
- Department of Pharmaceutical Biotechnology, School of Pharmacy, University of Pecs, Pecs, Hungary.,Szentagothai Research Center, University of Pecs, Pecs, Hungary
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Li Z, Zhang K, Li X, Pan H, Li S, Chen F, Zhang J, Zheng Z, Wang J, Liu H. Wnt5a suppresses inflammation-driven intervertebral disc degeneration via a TNF-α/NF-κB-Wnt5a negative-feedback loop. Osteoarthritis Cartilage 2018; 26:966-977. [PMID: 29656141 DOI: 10.1016/j.joca.2018.04.002] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2017] [Revised: 04/02/2018] [Accepted: 04/04/2018] [Indexed: 02/02/2023]
Abstract
OBJECTIVE This study was to investigate the molecular role of Wnt5a on inflammation-driven intervertebral disc degeneration (IVDD). METHODS The expression of Wnt5a was analyzed in human nucleus pulposus (NP) tissues with immunohistochemical staining. The effects of Wnt5a on matrix production were assessed by RT-qPCR and western blotting. Small interfering RNAs (siRNAs), promoter deletion assay, and promoter binding site mutant were used to reveal the molecular role of Wnt5a in TNF-α-induced matrix metalloproteinase (MMP) expression. The regulatory effects of TNF-α on Wnt5a were investigated with pharmachemical inhibitors and siRNA experiment. RESULTS The expression of Wnt5a was elevated in moderately degenerated human NP tissue with similar expression pattern of TNF-α. In NP cells, Wnt5a significantly increased aggrecan and collagen II expression. Inhibition of JNK or interfering Sox9 gene expression significantly suppressed Wnt5a-induced matrix production. AP-1(JunB) binding sites were located in Sox9 promoter and mutation of these sites sabotaged Wnt5a-induced Sox9 up-regulation and subsequent matrix genes expression. Notably, Wnt5a, which was induced by TNF-α, on the other way round suppressed TNF-α-NF-κB (p65) signaling and subsequent MMPs expression. In vivo studies with MR imaging confirmed the protective role of Wnt5a in IVDD. CONCLUSIONS Wnt5a, which can be induced by TNF-α, increased matrix production in a Sox9-dependent manner through the activation of JNK-AP1 (JunB) signaling, and antagonized TNF-α-induced up-regulation of MMPs through the inhibition of NF-κB signaling. It indicates that Wnt5a suppresses IVDD through a TNF-α/NF-κB-Wnt5a negative-feedback loop.
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Affiliation(s)
- Z Li
- Department of Spine Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China.
| | - K Zhang
- Department of Orthopedic Surgery, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, 519000, China.
| | - X Li
- Department of Spine Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China.
| | - H Pan
- Department of Spine Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China.
| | - S Li
- Department of Orthopedic Surgery, Guangzhou Chest Hospital, Guangzhou, 510080, China.
| | - F Chen
- Department of Spine Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China.
| | - J Zhang
- Department of Spine Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China.
| | - Z Zheng
- Department of Spine Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China.
| | - J Wang
- Department of Spine Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China.
| | - H Liu
- Department of Spine Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China.
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Meyer IS, Jungmann A, Dieterich C, Zhang M, Lasitschka F, Werkmeister S, Haas J, Müller OJ, Boutros M, Nahrendorf M, Katus HA, Hardt SE, Leuschner F. The cardiac microenvironment uses non-canonical WNT signaling to activate monocytes after myocardial infarction. EMBO Mol Med 2018; 9:1279-1293. [PMID: 28774883 PMCID: PMC5582413 DOI: 10.15252/emmm.201707565] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/04/2022] Open
Abstract
A disturbed inflammatory response following myocardial infarction (MI) is associated with poor prognosis and increased tissue damage. Monocytes are key players in healing after MI, but little is known about the role of the cardiac niche in monocyte activation. This study investigated microenvironment‐dependent changes in inflammatory monocytes after MI. RNA sequencing analysis of murine Ly6Chigh monocytes on day 3 after MI revealed differential regulation depending on location. Notably, the local environment strongly impacted components of the WNT signaling cascade. Analysis of WNT modulators revealed a strong upregulation of WNT Inhibitory Factor 1 (WIF1) in cardiomyocytes—but not fibroblasts or endothelial cells—upon hypoxia. Compared to wild‐type (WT) littermates, WIF1 knockout mice showed severe adverse remodeling marked by increased scar size and reduced ejection fraction 4 weeks after MI. While FACS analysis on day 1 after MI revealed no differences in neutrophil numbers, the hearts of WIF1 knockouts contained significantly more inflammatory monocytes than hearts from WT animals. Next, we induced AAV‐mediated cardiomyocyte‐specific WIF1 overexpression, which attenuated the monocyte response and improved cardiac function after MI, as compared to control‐AAV‐treated animals. Finally, WIF1 overexpression in isolated cardiomyocytes limited the activation of non‐canonical WNT signaling and led to reduced IL‐1β and IL‐6 expression in monocytes/macrophages. Taken together, we investigated the cardiac microenvironment's interaction with recruited monocytes after MI and identified a novel mechanism of monocyte activation. The local initiation of non‐canonical WNT signaling shifts the accumulating myeloid cells toward a pro‐inflammatory state and impacts healing after myocardial infarction.
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Affiliation(s)
- Ingmar Sören Meyer
- Department of Medicine III, University of Heidelberg, Heidelberg, Germany.,DZHK (German Centre for Cardiovascular Research), Partnersite, Heidelberg/Mannheim, Germany
| | - Andreas Jungmann
- Department of Medicine III, University of Heidelberg, Heidelberg, Germany
| | - Christoph Dieterich
- Department of Medicine III, University of Heidelberg, Heidelberg, Germany.,DZHK (German Centre for Cardiovascular Research), Partnersite, Heidelberg/Mannheim, Germany
| | - Min Zhang
- Department of Medicine III, University of Heidelberg, Heidelberg, Germany
| | - Felix Lasitschka
- Institute of Pathology, University of Heidelberg, Heidelberg, Germany.,Tissue Bank of the National Center for Tumor Diseases (NCT), Heidelberg, Germany
| | - Susann Werkmeister
- Department of Medicine III, University of Heidelberg, Heidelberg, Germany
| | - Jan Haas
- Department of Medicine III, University of Heidelberg, Heidelberg, Germany.,DZHK (German Centre for Cardiovascular Research), Partnersite, Heidelberg/Mannheim, Germany
| | - Oliver J Müller
- Department of Medicine III, University of Heidelberg, Heidelberg, Germany.,DZHK (German Centre for Cardiovascular Research), Partnersite, Heidelberg/Mannheim, Germany
| | - Michael Boutros
- DZHK (German Centre for Cardiovascular Research), Partnersite, Heidelberg/Mannheim, Germany.,Division Signaling and Functional Genomics, German Cancer Research Center (DKFZ) and Heidelberg University, Heidelberg, Germany
| | - Matthias Nahrendorf
- Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Hugo A Katus
- Department of Medicine III, University of Heidelberg, Heidelberg, Germany.,DZHK (German Centre for Cardiovascular Research), Partnersite, Heidelberg/Mannheim, Germany
| | - Stefan E Hardt
- Department of Medicine III, University of Heidelberg, Heidelberg, Germany
| | - Florian Leuschner
- Department of Medicine III, University of Heidelberg, Heidelberg, Germany .,DZHK (German Centre for Cardiovascular Research), Partnersite, Heidelberg/Mannheim, Germany
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Sugiuchi A, Sano Y, Furusawa M, Abe S, Muramatsu T. Human Dental Pulp Cells Express Cellular Markers for Inflammation and Hard Tissue Formation in Response to Bacterial Information. J Endod 2018; 44:992-996. [PMID: 29680724 DOI: 10.1016/j.joen.2018.02.022] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2017] [Revised: 12/05/2017] [Accepted: 02/23/2018] [Indexed: 11/15/2022]
Abstract
INTRODUCTION Lipopolysaccharide (LPS) is a major component of the outer membranes of gram-negative bacteria associated with deep dental caries and pulpitis. When bacteria invade dentinal tubes and dentin is continually destroyed, tertiary dentin is formed by preexisting odontoblasts. However, the relationship between LPS and tertiary dentin formation remains unclear. We investigated whether LPS stimulation induces the formation of hard tissue in human dental pulp cells (hDPCs). METHODS Immortalized hDPCs were cultured, and Escherichia coli-derived LPS (1 μg/mL) was incorporated into the culture medium. Samples were obtained after 0, 1, 3, 7, 14, and 21 days, and messenger RNA expression of IL-1β, IL-6, Wnt5a, Runx2, ALP, and alkaline phosphatase (ALP) activity was investigated. RESULTS Quantitative real-time polymerase chain reaction revealed higher messenger RNA expression levels of IL-1β and IL-6 in the LPS group on 1 day (P < .05). The expression levels of dentinogenesis-related markers including Wnt5a, Runx2, and ALP were higher in the LPS group (2.0-, 4.7- and 10.0-fold, respectively) than that in the control group at 14 days (P < .01). ALP activity was significantly stronger in the LPS group than in the control group at 21 days (P < .01). Treatment of Box5, an antagonist of Wnt5a, showed a decreased expression of Runx2 and ALP (P < .05). CONCLUSIONS These results indicate that LPS stimulation induces the gene expression of inflammatory cytokines and hard tissue formation through Wnt5a signaling pathways in hDPCs.
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Affiliation(s)
- Akina Sugiuchi
- Department of Endodontics, Tokyo Dental College, Tokyo, Japan
| | - Yousuke Sano
- Department of Endodontics, Tokyo Dental College, Tokyo, Japan
| | | | - Shu Abe
- Heiwa Dental Clinic, Tokyo, Japan
| | - Takashi Muramatsu
- Department of Operative Dentistry, Cariology and Pulp Biology, Tokyo Dental College, Tokyo, Japan.
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Shao Y, Zheng Q, Wang W, Xin N, Song X, Zhao C. Biological functions of macrophage-derived Wnt5a, and its roles in human diseases. Oncotarget 2018; 7:67674-67684. [PMID: 27608847 PMCID: PMC5341904 DOI: 10.18632/oncotarget.11874] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2015] [Accepted: 08/27/2016] [Indexed: 12/31/2022] Open
Abstract
Wnt5a is implicated in development and tissue homeostasis by activating β-catenin-independent pathway. Excessive production of Wnt5a is related to some human diseases. Macrophage recruitment is a character of inflammation and cancer, therefore macrophage-derived Wnt5a is supposed to be a player in these conditions. Actually, macrophage-derived Wnt5a maintains macrophage immune function, stimulates pro-inflammatory cytokine release, and induces angiogenesis and lymphangiogenesis. Furthermore, macrophage-derived Wnt5a is involved in insulin resistance, atherosclerosis and cancer. These findings indicate that macrophage-derived Wnt5a may be a target in the treatment of these diseases. Notably, unlike macrophages, the exact role of macrophage-derived Wnt5a in bacterial infection remains largely unknown.
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Affiliation(s)
- Yue Shao
- Department of Pathophysiology, College of Basic Medical Science, China Medical University, Shenyang, China
| | - Qianqian Zheng
- Department of Pathophysiology, College of Basic Medical Science, China Medical University, Shenyang, China
| | - Wei Wang
- Department of Pathophysiology, College of Basic Medical Science, China Medical University, Shenyang, China
| | - Na Xin
- Department of Pathophysiology, College of Basic Medical Science, China Medical University, Shenyang, China
| | - Xiaowen Song
- Department of Pathophysiology, College of Basic Medical Science, China Medical University, Shenyang, China
| | - Chenghai Zhao
- Department of Pathophysiology, College of Basic Medical Science, China Medical University, Shenyang, China
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49
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WNT5A induces castration-resistant prostate cancer via CCL2 and tumour-infiltrating macrophages. Br J Cancer 2018; 118:670-678. [PMID: 29381686 PMCID: PMC5846063 DOI: 10.1038/bjc.2017.451] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2016] [Revised: 11/13/2017] [Accepted: 11/15/2017] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND Although the standard treatment for the patients with recurrent and metastatic prostate cancer (CaP) is androgen deprivation therapy, castration-resistant prostate cancer (CRPC) eventually emerges. Our previous report indicated that bone morphogenetic protein 6 (BMP6) induced CRPC via tumour-infiltrating macrophages. In a separate line of study, we have observed that the WNT5A/BMP6 loop in CaP bone metastasis mediates resistance to androgen deprivation in tissue culture. Simultaneously, we have reported that BMP6 induced castration resistance in CaP cells via tumour-infiltrating macrophages. Therefore, our present study aims to investigate the mechanism of WNT5A and its interaction with macrophages on CRPC. METHODS Doxycycline inducible WNT5A overexpression prostate cancer cell line was used for detailed mechanical study. RESULTS WNT5A was associated with increased expression of chemokine ligand 2 (CCL2) in the human CaP cell line, LNCaP. Mechanistically, this induction of CCL2 by WNT5A is likely to be mediated via the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signalling pathway. Our in vivo experiments demonstrated that the overexpression of WNT5A in LNCaP cells promoted castration resistance. Conversely, this resistance was inhibited with the removal of macrophages via clodronate liposomes. When patient-derived CaP LuCaP xenografts were analysed, high levels of WNT5A were correlated with increased levels of CCL2 and BMP6. In addition, higher levels of CCL2 and BMP6 were more commonly observed in intra-femoral transplanted tumours as compared to subcutaneous-transplanted tumours in the patient-derived PCSD1 bone-niche model. CONCLUSIONS These findings collectively suggest that WNT5A may be a key gene that induces CRPC in the bone niche by recruiting and regulating macrophages through CCL2 and BMP6, respectively.
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50
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Miao P, Zhou XW, Wang P, Zhao R, Chen N, Hu CY, Chen XH, Qian L, Yu QW, Zhang JY, Xu R, He DY, Xiao LB, Li P, Lu M, Zhang DQ. Regulatory effect of anti-gp130 functional mAb on IL-6 mediated RANKL and Wnt5a expression through JAK-STAT3 signaling pathway in FLS. Oncotarget 2018; 9:20366-20376. [PMID: 29755657 PMCID: PMC5945543 DOI: 10.18632/oncotarget.23917] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2017] [Accepted: 12/11/2017] [Indexed: 12/22/2022] Open
Abstract
We investigated the effect on rheumatoid arthritis (RA) of an anti-gp130 monoclonal antibody (mAb) and its mechanism using RA fibroblast-like synoviocytes (FLS) and a collagen antibody–induced arthritis (CAIA) mouse model. We determined the interleukin 6 (IL-6), IL-6 receptor α (IL-6Rα), gp130, receptor activator of nuclear factor κB ligand (RANKL), matrix metalloproteinase 3 (MMP3), TIMP metallopeptidase inhibitor 1 (TIMP1), and Bcl-2 levels in RA and osteoarthritis (OA) serum and synovial fluid. RA FLS were cultured with or without IL-6/IL-6Rα; WNT5A and RANKL levels were detected. We generated an anti-gp130 mAb (M10) with higher affinity and specificity, blocked IL-6 signaling with it, and assessed its effects on the CAIA model, WNT5A and RANKL expression, and signal transducer and activator of transcription 3 (STAT3) phosphorylation. The IL-6 signaling system in patients with RA was increased; RANKL, MMP3, TIMP1, and Bcl-2 in RA bone were elevated. IL-6/IL-6Rα increased RA FLS WNT5A and RANKL expression. M10 ameliorated arthritis in the CAIA model, and inhibited RANKL, WNT5A, and Bcl-2 expression in RA FLS by blocking IL-6 signaling, likely via Janus kinase–STAT3 pathway downregulation. The IL-6–soluble IL-6Rα–gp130 complex is hyperactive in RA and OA. M10 may be the basis for a novel RA treatment drug.
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Affiliation(s)
- Ping Miao
- Department of Laboratory Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiao Wei Zhou
- Reproductive Medical Center of Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ping Wang
- Shanghai Jiao Tong University School of Medicine, XinHua Hospital, Shanghai, China.,Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Rong Zhao
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Department of Neurology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ninan Chen
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Department of Pediatrics, Ruijin Hospital and Ruijin Hospital North, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chao Ying Hu
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Central laboratory, Shanghai Xuhui Central Hospital, Shanghai, China
| | - Xue Hua Chen
- Department of Pediatrics, Ruijin Hospital and Ruijin Hospital North, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Liu Qian
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qi Wen Yu
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ji Ying Zhang
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Rong Xu
- Shanghai Guanghua Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai, China
| | - Dong Yi He
- Shanghai Guanghua Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai, China
| | - Lian Bo Xiao
- Shanghai Guanghua Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai, China
| | - Pu Li
- Department of Pediatrics, Ruijin Hospital and Ruijin Hospital North, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | | | - Dong Qing Zhang
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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