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Saadh MJ, Muhammad FA, Albadr RJ, Sanghvi G, Ballal S, Pathak PK, Bareja L, Aminov Z, Taher WM, Alwan M, Jawad MJ, Al-Nuaimi AMA. Exosomal non-coding RNAs: key regulators of inflammation-related cardiovascular disorders. Eur J Med Res 2025; 30:395. [PMID: 40390035 PMCID: PMC12087048 DOI: 10.1186/s40001-025-02649-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2025] [Accepted: 04/30/2025] [Indexed: 05/21/2025] Open
Abstract
Inflammation is a complex, tightly regulated process involving biochemical and cellular reactions to harmful stimuli. Often termed "the internal fire", it is crucial for protecting the body and facilitating tissue healing. While inflammation is essential for survival, chronic inflammation can be detrimental, leading to tissue damage and reduced survival. The innate immune system triggers inflammation, closely linked to the development of heart diseases, with significant consequences for individuals. Inflammation in arterial walls or the body substantially contributes to atherosclerotic disease progression, affecting the cardiovascular system. Altered lipoproteins increase the risk of excessive blood clotting, a hallmark of atherosclerotic cardiovascular disease and its complications. Integrating inflammatory biomarkers with established risk assessment techniques can enhance our ability to identify at-risk individuals, assess their risk severity, and recommend appropriate CVD prevention strategies. Exosomes, a type of extracellular vesicle, are released by various cells and mediate cell communication locally and systemically. In the past decade, exosomes have been increasingly studied for their vital roles in health maintenance and disease processes. They can transport substances like non-coding RNAs, lipids, and proteins between cells, influencing immune responses and inflammation to elicit harmful or healing effects. This study focuses on the critical role of inflammation in heart disease progression and how non-coding RNAs in exosomes modulate the inflammatory process, either exacerbating or alleviating inflammation-related damage in the cardiovascular system.
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Affiliation(s)
- Mohamed J Saadh
- Faculty of Pharmacy, Middle East University, Amman, 11831, Jordan
| | | | | | - Gaurav Sanghvi
- Marwadi University Research Center, Department of Microbiology, Faculty of Science, Marwadi University, Rajkot, Gujarat, 360003, India
| | - Suhas Ballal
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to Be University), Bangalore, Karnataka, India
| | - Piyus Kumar Pathak
- Department of Applied Sciences-Chemistry, NIMS Institute of Engineering & Technology, NIMS University Rajasthan, Jaipur, India
| | - Lakshay Bareja
- Centre for Research Impact & Outcome, Chitkara University Institute of Engineering and Technology, Chitkara University, Rajpura, Punjab, 140401, India
| | - Zafar Aminov
- Department of Public Health and Healthcare Management, Samarkand State Medical University, 18 Amir Temur Street, Samarkand, Uzbekistan
| | - Waam Mohammed Taher
- College of Nursing, National University of Science and Technology, Dhi Qar, Iraq
| | - Mariem Alwan
- Pharmacy College, Al-Farahidi University, Baghdad, Iraq
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Janczi T, Böhm B, Fehrl Y, Hartl N, Behrens F, Kinne RW, Burkhardt H, Meier F. Mechanical forces trigger invasive behavior in synovial fibroblasts through N-cadherin/ADAM15 -dependent modulation of LncRNA H19. Sci Rep 2025; 15:9814. [PMID: 40118917 PMCID: PMC11928650 DOI: 10.1038/s41598-025-94012-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Accepted: 03/11/2025] [Indexed: 03/24/2025] Open
Abstract
Joint damage caused by immune-mediated inflammation in rheumatoid arthritis (RA) preferentially affects site-specific mechano-sensitive areas. The perception of physical forces in the synovial tissue by the residing fibroblasts initiates signalling responses with impact on cellular functions. Here, we describe a mechanotransduction pathway in rheumatoid arthritis synovial fibroblasts (RASF), which is critically dependent on the disintegrin metalloproteinase ADAM15 and N-cadherin (NCAD). Both molecules co-localize in NCAD-based adherens junctions and trigger mechanosignaling events involving the activation of p21-activated kinase 2 (PAK2). The mechanically induced phosphorylation of PAK2 subsequently leads to its co-recruitment together with the adaptor molecule Nck to the NCAD/ADAM15 complex at the cell membrane. These signal transduction events initiate strain-induced downregulation of lncRNA H19 and miR-130a-3p. They finally result in an upregulation of cadherin-11 (CDH11), thereby enhancing cell invasive properties - a feature characteristic of aggressive RASFs. Accordingly, we propose a new mechano-induced pathway that causes an altered composition of cadherin expression in the adherens junctions of synovial fibroblasts and likely contributes to the site-specific variability of the aggressive RASF-phenotype in RA-pathogenesis.
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Affiliation(s)
- Tomasz Janczi
- Division of Rheumatology, University Hospital Frankfurt, Goethe University Frankfurt am Main, 60590, Frankfurt am Main, Germany
| | - Beate Böhm
- Division of Rheumatology, University Hospital Frankfurt, Goethe University Frankfurt am Main, 60590, Frankfurt am Main, Germany.
| | - Yuliya Fehrl
- Division of Rheumatology, University Hospital Frankfurt, Goethe University Frankfurt am Main, 60590, Frankfurt am Main, Germany
| | - Nikolas Hartl
- Division of Rheumatology, University Hospital Frankfurt, Goethe University Frankfurt am Main, 60590, Frankfurt am Main, Germany
| | - Frank Behrens
- Division of Rheumatology, University Hospital Frankfurt, Goethe University Frankfurt am Main, 60590, Frankfurt am Main, Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, 60590, Frankfurt am Main, Germany
| | - Raimund W Kinne
- Experimental Rheumatology Unit, Department of Orthopedics, Jena University Hospital, Waldkliniken Eisenberg GmbH, 07607, Eisenberg, Germany
| | - Harald Burkhardt
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, 60590, Frankfurt am Main, Germany
| | - Florian Meier
- Division of Rheumatology, University Hospital Frankfurt, Goethe University Frankfurt am Main, 60590, Frankfurt am Main, Germany
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Wang R, Mehrjou B, Dehghan‐Banian D, Wang BYH, Li Q, Deng S, Liu C, Zhang Z, Zhu Y, Wang H, Li D, Lu X, Cheng JCY, Ong MTY, Chan HF, Li G, Chu PK, Lee WYW. Targeting Long Noncoding RNA H19 in Subchondral Bone Osteocytes and the Alleviation of Cartilage Degradation in Osteoarthritis. Arthritis Rheumatol 2025; 77:283-297. [PMID: 39482250 PMCID: PMC11865692 DOI: 10.1002/art.43028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Revised: 08/22/2024] [Accepted: 09/13/2024] [Indexed: 11/03/2024]
Abstract
OBJECTIVE Emerging evidence suggests long noncoding RNA H19 is associated with osteoarthritis (OA) pathology. However, how H19 contributes to OA has not been reported. This study aims to investigate the biologic function of H19 in OA subchondral bone remodeling and OA progression. METHODS Clinical joint samples and OA animal models induced by surgical destabilization of the medial meniscus (DMM) were used to verify the causal relationship between osteocyte H19 and OA subchondral bone and cartilage changes. MLO-Y4 osteocyte cells subjected to fluid shear stress were used to verify the mechanism underlying H19-mediated mechanoresponse. Finally, the antisense oligonucleotide (ASO) against H19 was delivered to mice knee joints by magnetic metal-organic framework (MMOF) nanoparticles to develop a site-specific delivery method for targeting osteocyte H19 for OA treatment. RESULTS Both clinical OA subchondral bone and wildtype mice with DMM-induced OA exhibit aberrant higher subchondral bone mass, with more H19 mice expressing osteocytes. On the contrary, mice with osteocyte-specific deletion of H19 are less vulnerable to DMM-induced OA phenotype. In MLO-Y4 cells, H19-mediated osteocyte mechanoresponse through PI3K/AKT/GSK3 signal activation by EZH2-induced H3K27me3 regulation on protein phosphatase 2A inhibition. Targeted inhibition of H19 (using ASO-loaded MMOF) substantially alleviates subchondral bone remodeling and OA phenotype. CONCLUSION In summary, our results provide new evidence that the elevated H19 expression in osteocytes may contribute to aberrant subchondral bone remodeling and OA progression. H19 appears to be required for the osteocyte response to mechanical stimulation, and targeting H19 represents a new promising approach for OA treatment.
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Grants
- 2020 Rising Star Award, American Society for Bone and Mineral Research
- AoE/M-402/20 Area of Excellence, University Grants Committee, Hong Kong SAR
- Start-up Fund, The Chinese University of Hong Kong, Hong Kong SAR
- Matching Grant Scheme, University Grants Committee, Hong Kong SAR
- 2412162 General Research Fund, University Grants Committee, Hong Kong SAR
- CT1.1 Center for Neuromusculoskeletal Restorative Medicine, Health@InnoHK Program, Innovation Technology Commission, Hong Kong SAR
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Affiliation(s)
- Rongliang Wang
- Department of Orthopaedics and Traumatology, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China; Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China; SH Ho Scoliosis Research Laboratory, Joint Scoliosis Research Center of the Chinese University of Hong Kong and Nanjing University, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China; and State Key Laboratory of Pharmaceutical Biotechnology, Division of Sports Medicine and Adult Reconstructive Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical SchoolNanjingChina
| | - Babak Mehrjou
- Department of Physics, Department of Materials Science and Engineering, Department of Biomedical EngineeringCity University of Hong KongTat Chee AvenueKowloonHong Kong SARChina
| | - Dorsa Dehghan‐Banian
- Department of Orthopaedics and Traumatology, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China, and Li Ka Shing Institute of Health SciencesThe Chinese University of Hong KongShatinHong Kong SARChina
| | - Belle Yu Hsuan Wang
- Department of Orthopaedics and Traumatology, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China; Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China; and Center for Neuromusculoskeletal Restorative MedicineCUHK InnoHK Centres, Hong Kong Science ParkHong Kong SARChina
| | - Qiangqiang Li
- Department of Orthopaedics and Traumatology, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China; Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China; SH Ho Scoliosis Research Laboratory, Joint Scoliosis Research Center of the Chinese University of Hong Kong and Nanjing University, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China; and State Key Laboratory of Pharmaceutical Biotechnology, Division of Sports Medicine and Adult Reconstructive Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical SchoolNanjingChina
| | - Shuai Deng
- Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China, and Key Laboratory for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of MedicineThe Chinese University of Hong KongHong Kong SARChina
| | - Chuanhai Liu
- Center for Neuromusculoskeletal Restorative Medicine, CUHK InnoHK Centres, Hong Kong Science Park, Hong Kong SAR, China; Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China; and Key Laboratory for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of MedicineThe Chinese University of Hong KongHong Kong SARChina
| | - Zhe Zhang
- Department of Orthopaedics and Traumatology, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China; Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China; and SH Ho Scoliosis Research LaboratoryJoint Scoliosis Research Center of the Chinese University of Hong Kong and Nanjing University, The Chinese University of Hong Kong, ShatinHong Kong SARChina
| | - Yanlun Zhu
- Center for Neuromusculoskeletal Restorative Medicine, CUHK InnoHK Centres, Hong Kong Science Park, Hong Kong SAR, China; Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China; and Key Laboratory for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of MedicineThe Chinese University of Hong KongHong Kong SARChina
| | - Haixing Wang
- Department of Orthopaedics and Traumatology, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China, and Li Ka Shing Institute of Health SciencesThe Chinese University of Hong KongShatinHong Kong SARChina
| | - Dan Li
- Department of Physics, Department of Materials Science and Engineering, Department of Biomedical EngineeringCity University of Hong KongTat Chee AvenueKowloonHong Kong SARChina
| | - Xiaomin Lu
- Department of Orthopaedics and Traumatology, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China, and Li Ka Shing Institute of Health SciencesThe Chinese University of Hong KongShatinHong Kong SARChina
| | - Jack Chun Yiu Cheng
- Department of Orthopaedics and Traumatology, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China, and SH Ho Scoliosis Research LaboratoryJoint Scoliosis Research Center of the Chinese University of Hong Kong and Nanjing University, The Chinese University of Hong Kong, ShatinHong Kong SARChina
| | - Michael Tim Yun Ong
- Department of Orthopaedics and Traumatology, Faculty of Medicine, Prince of Wales HospitalThe Chinese University of Hong Kong, ShatinHong Kong SARChina
| | - Hon Fai Chan
- Center for Neuromusculoskeletal Restorative Medicine, CUHK InnoHK Centres, Hong Kong Science Park, Hong Kong SAR, China; Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China; and Key Laboratory for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of MedicineThe Chinese University of Hong KongHong Kong SARChina
| | - Gang Li
- Department of Orthopaedics and Traumatology, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China, and Li Ka Shing Institute of Health SciencesThe Chinese University of Hong KongShatinHong Kong SARChina
| | - Paul K. Chu
- Department of Physics, Department of Materials Science and Engineering, Department of Biomedical EngineeringCity University of Hong KongTat Chee AvenueKowloonHong Kong SARChina
| | - Wayne Yuk Wai Lee
- Department of Orthopaedics and Traumatology, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China; Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China; SH Ho Scoliosis Research Laboratory, Joint Scoliosis Research Center of the Chinese University of Hong Kong and Nanjing University, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China; and Center for Neuromusculoskeletal Restorative Medicine, CUHK InnoHK Centres, Hong Kong Science ParkHong Kong SARChina
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Ketenci A. Rheumatoid arthritis treatment: Is exercise a game changer? Turk J Phys Med Rehabil 2024; 70:415-426. [PMID: 40028397 PMCID: PMC11868869 DOI: 10.5606/tftrd.2024.16088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Accepted: 11/19/2024] [Indexed: 03/05/2025] Open
Abstract
It is known that physical activity and exercise have many effects on patients with rheumatoid arthritis, such as reducing pain, stiffness, and fatigue and having positive effects on the development of complications related to the disease. However, despite all this information, the level of exercise and physical activity in patients with rheumatoid arthritis is lower than in healthy individuals. This may be due to reasons such as thinking that the disease will worsen, not having enough information about exercises, and not being supported enough by healthcare professionals and family in this regard. This review summarized the basic effects of exercises and recommended exercise programs.
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Affiliation(s)
- Ayşegül Ketenci
- Department of Physical Medicine and Rehabilitation, Koç University Faculty of Medicine, İstanbul, Türkiye
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5
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Hu K, Wen H, Song T, Che Z, Song Y, Song M. Deciphering the Role of LncRNAs in Osteoarthritis: Inflammatory Pathways Unveiled. J Inflamm Res 2024; 17:6563-6581. [PMID: 39318993 PMCID: PMC11421445 DOI: 10.2147/jir.s489682] [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: 08/02/2024] [Accepted: 09/17/2024] [Indexed: 09/26/2024] Open
Abstract
Long non-coding RNA (LncRNA), with transcripts over 200 nucleotides in length, play critical roles in numerous biological functions and have emerged as significant players in the pathogenesis of osteoarthritis (OA), an inflammatory condition traditionally viewed as a degenerative joint disease. This review comprehensively examines the influence of LncRNA on the inflammatory processes driving OA progression, focusing on their role in regulating gene expression, cellular activities, and inflammatory pathways. Notably, LncRNAs such as MALAT1, H19, and HOTAIR are upregulated in OA and exacerbate the inflammatory milieu by modulating key signaling pathways like NF-κB, TGF-β/SMAD, and Wnt/β-catenin. Conversely, LncRNA like MEG3 and GAS5, which are downregulated in OA, show potential in dampening inflammatory responses and protecting against cartilage degradation by influencing miRNA interactions and cytokine production. By enhancing our understanding of LncRNA' roles in OA inflammation, we can better leverage them as potential biomarkers for the disease and develop innovative therapeutic strategies for OA management. This paper aims to delineate the mechanisms by which LncRNA influence inflammatory responses in OA and propose them as novel targets for therapeutic intervention.
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Affiliation(s)
- Kangyi Hu
- Clinical College of Traditional Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou, People’s Republic of China
| | - Haonan Wen
- Clinical College of Traditional Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou, People’s Republic of China
| | - Ting Song
- Clinical College of Traditional Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou, People’s Republic of China
| | - Zhixin Che
- Clinical College of Traditional Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou, People’s Republic of China
| | - Yongjia Song
- Clinical College of Traditional Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou, People’s Republic of China
| | - Min Song
- Clinical College of Traditional Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou, People’s Republic of China
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6
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Zhou XC, Wang DX, Zhang CY, Yang YJ, Zhao RB, Liu SY, Ni GX. Exercise promotes osteogenic differentiation by activating the long non-coding RNA H19/microRNA-149 axis. World J Orthop 2024; 15:363-378. [PMID: 38680671 PMCID: PMC11045468 DOI: 10.5312/wjo.v15.i4.363] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 02/04/2024] [Accepted: 03/19/2024] [Indexed: 04/16/2024] Open
Abstract
BACKGROUND Regular physical activity during childhood and adolescence is beneficial to bone development, as evidenced by the ability to increase bone density and peak bone mass by promoting bone formation. AIM To investigate the effects of exercise on bone formation in growing mice and to investigate the underlying mechanisms. METHODS 20 growing mice were randomly divided into two groups: Con group (control group, n = 10) and Ex group (treadmill exercise group, n = 10). Hematoxylin-eosin staining, immunohistochemistry, and micro-CT scanning were used to assess the bone formation-related indexes of the mouse femur. Bioinformatics analysis was used to find potential miRNAs targets of long non-coding RNA H19 (lncRNA H19). RT-qPCR and Western Blot were used to confirm potential miRNA target genes of lncRNA H19 and the role of lncRNA H19 in promoting osteogenic differentiation. RESULTS Compared with the Con group, the expression of bone morphogenetic protein 2 was also significantly increased. The micro-CT results showed that 8 wk moderate-intensity treadmill exercise significantly increased bone mineral density, bone volume fraction, and the number of trabeculae, and decreased trabecular segregation in the femur of mice. Inhibition of lncRNA H19 significantly upregulated the expression of miR-149 and suppressed the expression of markers of osteogenic differentiation. In addition, knockdown of lncRNA H19 significantly downregulated the expression of autophagy markers, which is consistent with the results of autophagy-related protein changes detected in mouse femurs by immunofluorescence. CONCLUSION Appropriate treadmill exercise can effectively stimulate bone formation and promote the increase of bone density and bone volume in growing mice, thus enhancing the peak bone mass of mice. The lncRNA H19/miR-149 axis plays an important regulatory role in osteogenic differentiation.
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Affiliation(s)
- Xu-Chang Zhou
- School of Sport Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, China
| | - Dong-Xue Wang
- School of Sport Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, China
| | - Chun-Yu Zhang
- School of Sport Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, China
| | - Ya-Jing Yang
- Department of Acupuncture and Moxibustion, Hubei University of Chinese Medicine, Wuhan 430065, Hubei Province, China
| | - Ruo-Bing Zhao
- School of Sport Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, China
| | - Sheng-Yao Liu
- Department of Spinal Surgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, Guangdong Province, China
| | - Guo-Xin Ni
- Department of Rehabilitation Medicine, The First Affiliated Hospital of Xiamen University, Xiamen 361003, Fujian Province, China
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7
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Tian R, Ghosh S. Mechanisms and functions of lncRNAs linked to autoimmune disease risk alleles. Adv Immunol 2024; 161:1-15. [PMID: 38763698 DOI: 10.1016/bs.ai.2024.03.006] [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] [Indexed: 05/21/2024]
Abstract
Recent advances in human genomics technologies have helped uncover genetic risk alleles for many complex autoimmune diseases. Intriguingly, over 90% of genome-wide association study (GWAS) risk alleles reside within the non-coding regions of the genome. An emerging new frontier of functional and mechanistic studies have shed light on the functional relevance of risk alleles that lie within long noncoding RNAs (lncRNAs). Here, we review the mechanisms and functional implications of five evolutionarily conserved lncRNAs that display risk allele association with highly prevalent autoimmune diseases.
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Affiliation(s)
- Ruxiao Tian
- Department of Microbiology & Immunology, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, United States
| | - Sankar Ghosh
- Department of Microbiology & Immunology, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, United States.
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8
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Sarangi P, Senthilkumar MB, Kumar N, Senguttuvan S, Vasudevan M, Jayandharan GR. Potential role of long non-coding RNA H19 and Neat1 in haemophilic arthropathy. J Cell Mol Med 2023; 27:1745-1749. [PMID: 37183540 PMCID: PMC10273061 DOI: 10.1111/jcmm.17770] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Revised: 04/11/2023] [Accepted: 05/04/2023] [Indexed: 05/16/2023] Open
Affiliation(s)
- Pratiksha Sarangi
- Department of Biological Sciences and BioengineeringIndian Institute of TechnologyKanpurIndia
| | | | - Narendra Kumar
- Department of Biological Sciences and BioengineeringIndian Institute of TechnologyKanpurIndia
| | | | - Madavan Vasudevan
- Genomics and Data ScienceTheomics International Pvt Ltd.BangaloreIndia
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9
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Elazazy O, Midan HM, Shahin RK, Elesawy AE, Elballal MS, Sallam AAM, Elbadry AMM, Elrebehy MA, Bhnsawy A, Doghish AS. Long non-coding RNAs and rheumatoid arthritis: Pathogenesis and clinical implications. Pathol Res Pract 2023; 246:154512. [PMID: 37172525 DOI: 10.1016/j.prp.2023.154512] [Citation(s) in RCA: 39] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 05/04/2023] [Accepted: 05/05/2023] [Indexed: 05/15/2023]
Abstract
Long non-coding RNAs (lncRNAs) are a class of noncoding RNAs with a length larger than 200 nucleotides that participate in various diseases and biological processes as they can control gene expression by different mechanisms. Rheumatoid arthritis (RA) is an inflammatory autoimmune disorder characterized by symmetrical destructive destruction of distal joints as well as extra-articular involvement. Different studies have documented and proven the abnormal expression of lncRNAs in RA patients. Various lncRNAs have proven potential as biomarkers and targets for diagnosing, prognosis and treating RA. This review will focus on RA pathogenesis, clinical implications, and related lncRNA expressions that help to identify new biomarkers and treatment targets.
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Affiliation(s)
- Ola Elazazy
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr, Cairo 11829, Egypt
| | - Heba M Midan
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr, Cairo 11829, Egypt
| | - Reem K Shahin
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr, Cairo 11829, Egypt
| | - Ahmed E Elesawy
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr, Cairo 11829, Egypt
| | - Mohammed S Elballal
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr, Cairo 11829, Egypt
| | - Al-Aliaa M Sallam
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr, Cairo 11829, Egypt
| | - Abdullah M M Elbadry
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr, Cairo 11829, Egypt
| | - Mahmoud A Elrebehy
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr, Cairo 11829, Egypt.
| | - Abdelmenem Bhnsawy
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr, Cairo 11829, Egypt
| | - Ahmed S Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr, Cairo 11829, Egypt; Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr, Cairo 11231, Egypt.
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10
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Esawy MM, Ebaid AM, Abd-Elhameed A, Thagfan FA, Mubaraki MA, Alazzouni AS, Dkhil MA, Shabana MA. Assessment of Circulating lncRNA H19 in Ankylosing Spondylitis Patients and Its Correlation with Disease Activity. J Pers Med 2023; 13:914. [PMID: 37373903 DOI: 10.3390/jpm13060914] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 05/23/2023] [Accepted: 05/25/2023] [Indexed: 06/29/2023] Open
Abstract
Ankylosing spondylitis (AS) is a chronic inflammatory disease that results in severe pain and stiffness in the joints. The causes and pathophysiology of AS are still largely unknown. The lncRNA H19 plays key roles in the pathogenesis of AS by mediating inflammatory progression by acting in the axis of IL-17A/IL-23. The aims of this study were determining the role of lncRNA H19 in AS and assessing its clinical correlation. A case-control study was conducted and qRT-PCR was utilized to measure H19 expression. Comparing AS cases to healthy controls, it was found that H19 expression was significantly upregulated. For AS prediction, H19 demonstrated a 81.1% sensitivity, 100% specificity, and 90.6% diagnostic accuracy at a lncRNA H19 expression value of 1.41. lncRNA H19 had a significantly positive correlation with AS activity, MRI results, and inflammatory markers. lncRNA H19 seemed to be an independent predictor of AS (adjusted OR of 211 (95% CI: 4.7-939; p = 0.025)). After 3 months of clinical follow-up, seventeen patients (32.1%) showed minimal clinical improvement and fifteen patients (28.3%) showed major improvement. AS activity scores were significantly decreased in patients with high H19 expression. A significantly elevated lncRNA H19 expression was observed in AS cases compared with that in healthy controls. These results suggest that upregulation of lncRNA H19 expression may be involved in the pathogenesis of AS. The expression of the lncRNA H19 is related to the duration and activity of the disease. LncRNA H19 expression seems to be an independent predictor of AS.
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Affiliation(s)
- Marwa M Esawy
- Clinical Pathology Department, Faculty of Human Medicine, Zagazig University, Zagazig 44519, Egypt
| | - Amany M Ebaid
- Rheumatology and Rehabilitation Department, Faculty of Human Medicine, Zagazig University, Zagazig 44519, Egypt
| | - Amir Abd-Elhameed
- Internal Medicine Department, Faculty of Human Medicine, Zagazig University, Zagazig 44519, Egypt
| | - Felwa A Thagfan
- Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, Riyadh 11671, Saudi Arabia
| | - Murad A Mubaraki
- Clinical Laboratory Sciences Department, College of Applied Medical Sciences, King Saud University, Riyadh 12372, Saudi Arabia
| | - Ahmed S Alazzouni
- Department of Zoology and Entomology, Faculty of Science, Helwan University, Cairo 11795, Egypt
| | - Mohamed A Dkhil
- Department of Zoology and Entomology, Faculty of Science, Helwan University, Cairo 11795, Egypt
- Applied Science Research Center, Applied Science Private University, Amman 11931, Jordan
| | - Marwa A Shabana
- Clinical Pathology Department, Faculty of Human Medicine, Zagazig University, Zagazig 44519, Egypt
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11
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Rheumatoid arthritis and non-coding RNAs; how to trigger inflammation. Life Sci 2023; 315:121367. [PMID: 36639050 DOI: 10.1016/j.lfs.2023.121367] [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: 09/14/2022] [Revised: 12/31/2022] [Accepted: 12/31/2022] [Indexed: 01/12/2023]
Abstract
Rheumatoid arthritis (RA) is a systemic and chronic inflammatory disease categorized by continuous synovitis in the joints and systemic inflammatory responses that can cause lifelong disability. The major cause of RA is the dysregulation of the immune response. The development of RA disease includes multiplex association of several interleukins and cells, which leads to synovial cell growth, cartilage and bone damage. The primary stage of RA disease is related to the modification of both the innate and adaptive immune systems, which leads to the formation of autoantibodies. This process results in many damaged molecules and epitope spreading. Both the innate (e.g., dendritic cells, macrophages, and neutrophils) and acquired immune cells (e.g., T and B lymphocytes) will increase and continue the chronic inflammatory condition in the next stages of the RA disease. In recent years, non-coding RNAs have been proved as significant controllers of biological functions, especially immune cell expansion and reactions. Non-coding RNAs were primarily containing microRNA (miRNA), long non-coding RNA (lncRNA), and circular RNA (circRNA). Various studies confirmed non-coding RNAs as hopeful markers for diagnosing and curing RA. This review will describe and cover existing knowledge about RA pathogenesis, which might be favorable for discovering possible ncRNA markers for RA.
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12
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Li Z, Wang XQ. Clinical effect and biological mechanism of exercise for rheumatoid arthritis: A mini review. Front Immunol 2023; 13:1089621. [PMID: 36685485 PMCID: PMC9852831 DOI: 10.3389/fimmu.2022.1089621] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Accepted: 12/16/2022] [Indexed: 01/09/2023] Open
Abstract
Rheumatoid arthritis (RA) is a common systematic, chronic inflammatory, autoimmune, and polyarticular disease, causing a range of clinical manifestations, including joint swelling, redness, pain, stiffness, fatigue, decreased quality of life, progressive disability, cardiovascular problems, and other comorbidities. Strong evidence has shown that exercise is effective for RA treatment in various clinical domains. Exercise training for relatively longer periods (e.g., ≥ 12 weeks) can decrease disease activity of RA. However, the mechanism underlying the effectiveness of exercise in reducing RA disease activity remains unclear. This review first summarizes and highlights the effectiveness of exercise in RA treatment. Then, we integrate current evidence and propose biological mechanisms responsible for the potential effects of exercise on immune cells and immunity, inflammatory response, matrix metalloproteinases, oxidative stress, and epigenetic regulation. However, a large body of evidence was obtained from the non-RA populations. Future studies are needed to further examine the proposed biological mechanisms responsible for the effectiveness of exercise in decreasing disease activity in RA populations. Such knowledge will contribute to the basic science and strengthen the scientific basis of the prescription of exercise therapy for RA in the clinical routine.
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Affiliation(s)
- Zongpan Li
- Department of Sport Rehabilitation, Shanghai University of Sport, Shanghai, China
- Department of Sport Rehabilitation Medicine, Shanghai Shangti Orthopaedic Hospital, Shanghai, China
| | - Xue-Qiang Wang
- Department of Sport Rehabilitation, Shanghai University of Sport, Shanghai, China
- Department of Sport Rehabilitation Medicine, Shanghai Shangti Orthopaedic Hospital, Shanghai, China
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13
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Long noncoding RNA H19 synergizes with STAT1 to regulate SNX10 in rheumatoid arthritis. Mol Immunol 2023; 153:106-118. [PMID: 36459790 DOI: 10.1016/j.molimm.2022.11.018] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 10/24/2022] [Accepted: 11/21/2022] [Indexed: 12/02/2022]
Abstract
Erosive destruction of joint structures is an important event in the rheumatoid arthritis (RA) development where fibroblast-like synoviocytes (FLS) represent the main effectors. The implication of long noncoding RNAs (lncRNAs) in RA has not been clearly established. Here, we sought to assess the function of lncRNA H19 in RA by assessing its contribution to the phenotype of FLS. H19 was overexpressed in RA-FLS, and H19 promoted RA-FLS proliferation, invasion as well as angiogenesis and reduced RA-FLS apoptosis. Moreover, H19 loss significantly alleviated joint redness and swelling and reduced inflammatory response, synovial hyperplasia and cartilage damage in arthritic mice induced by collagen. Mechanistically, H19 significantly increased the transcription of sorting nexin (SNX) 10 in RA-FLS by promoting STAT1 translocation into the nucleus. Overexpression of SNX10 or STAT1 mitigated the repressing effects of H19 loss on RA in mice. Our findings highlight that H19 upregulation may result in the development of FLS-mediated RA via the STAT1/SNX10 axis. H19 might serve as a possible therapeutic target for RA treatment.
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Yang J, Li Z, Wang L, Yun X, Zeng Y, Ng JP, Lo H, Wang Y, Zhang K, Law BYK, Wong VKW. The role of non-coding RNAs (miRNA and lncRNA) in the clinical management of rheumatoid arthritis. Pharmacol Res 2022; 186:106549. [DOI: 10.1016/j.phrs.2022.106549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 11/04/2022] [Accepted: 11/06/2022] [Indexed: 11/09/2022]
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Ravaei A, Zimmer-Bensch G, Govoni M, Rubini M. lncRNA-mediated synovitis in rheumatoid arthritis: A perspective for biomarker development. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2022; 175:103-119. [PMID: 36126801 DOI: 10.1016/j.pbiomolbio.2022.09.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 07/28/2022] [Accepted: 09/13/2022] [Indexed: 06/15/2023]
Abstract
Long noncoding RNAs (lncRNAs) are a regulatory class of noncoding RNAs with a wide range of activities such as transcriptional and post-transcriptional regulations. Emerging evidence has demonstrated that various lncRNAs contribute to the initiation and progression of Rheumatoid Arthritis (RA) through distinctive mechanisms. The present study reviews the recent findings on lncRNA role in RA development. It focuses on the involvement of different lncRNAs in the main steps of RA pathogenesis including T cell activation, cytokine dysregulation, fibroblast-like synoviocyte (FLS) activation and joint destruction. Besides, it discusses the current findings on RA diagnosis and the potential of lncRNAs as diagnostic, prognostic and predictive biomarkers in Rheumatology clinic.
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Affiliation(s)
- Amin Ravaei
- Department of Neurosciences and Rehabilitation, Section of Medical Biochemistry, Molecular Biology and Genetics, University of Ferrara, Ferrara, Italy.
| | - Geraldine Zimmer-Bensch
- Division of Neuroepigenetics, Institute of Zoology (Biology II), RWTH Aachen University, Aachen, Germany.
| | - Marcello Govoni
- Department of Medical Science, Section of Rheumatology, University of Ferrara, Ferrara, Italy.
| | - Michele Rubini
- Department of Neurosciences and Rehabilitation, Section of Medical Biochemistry, Molecular Biology and Genetics, University of Ferrara, Ferrara, Italy.
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16
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Wang R, Shiu HT, Lee WYW. Emerging role of lncRNAs in osteoarthritis: An updated review. Front Immunol 2022; 13:982773. [PMID: 36304464 PMCID: PMC9593085 DOI: 10.3389/fimmu.2022.982773] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 09/08/2022] [Indexed: 11/22/2022] Open
Abstract
Osteoarthritis (OA) is a prevalent joint disease, which is associated with progressive articular cartilage loss, synovial inflammation, subchondral sclerosis and meniscus injury. The molecular mechanism underlying OA pathogenesis is multifactorial. Long non-coding RNAs (lncRNAs) are non-protein coding RNAs with length more than 200 nucleotides. They have various functions such as modulating transcription and protein activity, as well as forming endogenous small interfering RNAs (siRNAs) and microRNA (miRNA) sponges. Emerging evidence suggests that lncRNAs might be involved in the pathogenesis of OA which opens up a new avenue for the development of new biomarkers and therapeutic strategies. The purpose of this review is to summarize the current clinical and basic experiments related to lncRNAs and OA with a focus on the extensively studied H19, GAS5, MALAT1, XIST and HOTAIR. The potential translational value of these lncRNAs as therapeutic targets for OA is also discussed.
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Affiliation(s)
- Rongliang Wang
- Department of Orthopaedics and Traumatology, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
- Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
- SH Ho Scoliosis Research Laboratory, Joint Scoliosis Research Center of the Chinese University of Hong Kong and Nanjing University, The Chinese University of Hong Kong, Hong Kong, China
| | - Hoi Ting Shiu
- Department of Orthopaedics and Traumatology, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
- Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Wayne Yuk Wai Lee
- Department of Orthopaedics and Traumatology, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
- Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
- SH Ho Scoliosis Research Laboratory, Joint Scoliosis Research Center of the Chinese University of Hong Kong and Nanjing University, The Chinese University of Hong Kong, Hong Kong, China
- *Correspondence: Wayne Yuk Wai Lee,
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Association Between HOTAIR rs920778 and H19 rs3741219 Polymorphisms with Hashimoto's Thyroiditis (HT) and Graves' Disease (GD). Rep Biochem Mol Biol 2022; 11:377-385. [PMID: 36718300 PMCID: PMC9883025 DOI: 10.52547/rbmb.11.3.377] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 04/21/2022] [Indexed: 01/18/2023]
Abstract
Background Graves' disease (GD) and Hashimoto's thyroiditis (HT) are two autoimmune thyroid diseases (AITDs). The current study aimed to assess possible association between HOTAIR rs920778 and H19 rs3741219 polymorphisms with GD and HT. Methods We recruited 248 patients with autoimmune thyroid disease (133 HT patients and 115 GD patients) and 135 age- and sex-matched controls. The PCR-RFLP method was applied for genotyping of HOTAIR rs920778, and H19 rs3741219 polymorphisms. Results The HOTAIR rs920778 GA frequency was significantly higher in control compared to HT group. The Overdominant model showed a significant association with the risk of HT. However, no significant association was observed between this polymorphism and HT susceptibility in dominant and recessive models. The H19 rs3741219 GA was more repeated in HT patients compared to control group, but the difference was not significant. There was no association between HOTAIR rs920778 and H19 rs3741219 polymorphisms with GD in all genetic models. Discussion Our findings indicated that HOTAIR rs920778 polymorphism decreased the risk of HT. Since, this the first study, further studies with different races are required to confirm our results.
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Plewka P, Raczynska KD. Long Intergenic Noncoding RNAs Affect Biological Pathways Underlying Autoimmune and Neurodegenerative Disorders. Mol Neurobiol 2022; 59:5785-5808. [PMID: 35796900 PMCID: PMC9395482 DOI: 10.1007/s12035-022-02941-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Accepted: 06/23/2022] [Indexed: 11/25/2022]
Abstract
Long intergenic noncoding RNAs (lincRNAs) are a class of independently transcribed molecules longer than 200 nucleotides that do not overlap known protein-coding genes. LincRNAs have diverse roles in gene expression and participate in a spectrum of biological processes. Dysregulation of lincRNA expression can abrogate cellular homeostasis, cell differentiation, and development and can also deregulate the immune and nervous systems. A growing body of literature indicates their important and multifaceted roles in the pathogenesis of several different diseases. Furthermore, certain lincRNAs can be considered potential therapeutic targets and valuable diagnostic or prognostic biomarkers capable of predicting the onset of a disease, its degree of activity, or the progression phase. In this review, we discuss possible mechanisms and molecular functions of lincRNAs in the pathogenesis of selected autoimmune and neurodegenerative disorders: multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, Huntington's disease, Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. This summary can provide new ideas for future research, diagnosis, and treatment of these highly prevalent and devastating diseases.
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Affiliation(s)
- Patrycja Plewka
- Department of Gene Expression, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Poznan, Poland
- Center for Advanced Technology, Adam Mickiewicz University, Uniwersytetu Poznanskiego 10, 61-614, Poznan, Poland
| | - Katarzyna Dorota Raczynska
- Department of Gene Expression, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Poznan, Poland.
- Center for Advanced Technology, Adam Mickiewicz University, Uniwersytetu Poznanskiego 10, 61-614, Poznan, Poland.
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Non-coding RNA network associated with obesity and rheumatoid arthritis. Immunobiology 2022; 227:152281. [DOI: 10.1016/j.imbio.2022.152281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Accepted: 09/13/2022] [Indexed: 11/18/2022]
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H19 is involved in the regulation of inflammatory responses in acute gouty arthritis by targeting miR-2-3p. Immunol Res 2022; 70:392-399. [PMID: 35314952 DOI: 10.1007/s12026-022-09276-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Accepted: 03/10/2022] [Indexed: 11/05/2022]
Abstract
A great number of studies have confirmed that long noncoding RNA (lncRNA) are involved in the regulation of inflammatory response in acute gouty arthritis (AGA). This paper aimed to survey the regulatory mechanism of H19 on AGA. The expression of serum H19 in all subjects was examined by qRT-PCR. The ROC curve was used to estimate the diagnostic value of H19 for AGA. THP-1 cells were induced by MSU to establish in vitro AGA cell model. The concentrations of cytokines such as IL-1β, IL-8, and TNF-α were tested by ELISA. Luciferase reporter gene analysis was used to verify the interaction between H19 and the 3'-UTR of miR-22-3p. Expressions of serum H19 in AGA patients were significantly higher than that in controls. The ROC curve indicated the potential of H19 as a diagnostic marker for AGA. Cell experiments revealed that the downregulation of H19 significantly inhibited the expressions of IL-1β, IL-8, and TNF-α. The luciferase reporter gene assay manifested that miR-22-3p is the target gene of H19. And knockdown of miR-22-3p overturned the downregulation of inflammatory factors caused by H19 inhibition. H19 aggravated MSU-induced THP-1 inflammation by negatively targeting miR-22-3p, suggesting a new regulatory mechanism and potential therapeutic target for AGA.
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Amiri M, Mokhtari MJ, Bayat M, Safari A, Dianatpuor M, Tabrizi R, Borhani-Haghighi A. Expression and diagnostic values of MIAT, H19, and NRON long non-coding RNAs in multiple sclerosis patients. EGYPTIAN JOURNAL OF MEDICAL HUMAN GENETICS 2022. [DOI: 10.1186/s43042-022-00260-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Abstract
Background
Multiple sclerosis (MS) is a chronic inflammatory disease. Various long non-coding RNAs (lncRNAs) appear to have an important role in the pathophysiology of MS. This study aimed at evaluating the expression levels of lncRNAs, MIAT, H19, and NRON in peripheral blood of MS cases to a healthy control group. We collected blood samples of 95 MS cases (76 relapsing–remitting (RR) and 19 secondary progressive (SP) MS) and 95 controls. We used quantitative real-time PCR for the evaluation of gene expression. The correlation between expression with clinical parameters was analyzed by a multiple linear regression model. Receiver operating characteristic (ROC) curve analysis was carried out to detect the diagnostic potential of lncRNAs levels according to the area under the curve (AUC).
Results
MIAT, H19, and NRON were significantly increased in the RRMS and SPMS subgroups compared to the controls. We found that the H19 and MIAT expression significantly were higher in SPMS compared with RRMS. Patients with RRMS had a greater level of the average NRON expression is compared with SPMS patients. The expression level of H19 significantly was higher in females relative to male patients. Based on the area under curve (AUC) values, NRON had the best performance in the differentiation of MS patients from controls (AUC = 0.95, P < 0.0001). A combination of MIAT, H19, and NRON expression levels could be useful in differentiating MS patients with 93.6% sensitivity, 98.9% specificity, and diagnostic power of 0.96 (P < 0.0001).
Conclusions
The levels of MIAT, H19, and NRON in peripheral blood could be important biomarkers for MS diagnosis.
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22
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Emerging Role of LncRNAs in Autoimmune Lupus. Inflammation 2022; 45:937-948. [DOI: 10.1007/s10753-021-01607-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 11/11/2021] [Accepted: 12/05/2021] [Indexed: 12/13/2022]
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Wu H, Chen S, Li A, Shen K, Wang S, Wang S, Wu P, Luo W, Pan Q. LncRNA Expression Profiles in Systemic Lupus Erythematosus and Rheumatoid Arthritis: Emerging Biomarkers and Therapeutic Targets. Front Immunol 2022; 12:792884. [PMID: 35003113 PMCID: PMC8732359 DOI: 10.3389/fimmu.2021.792884] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Accepted: 12/07/2021] [Indexed: 12/29/2022] Open
Abstract
Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are two common multisystem autoimmune diseases that share, among others, many clinical manifestations and serological features. The role of long non-coding RNAs (lncRNAs) has been of particular interest in the pathogenesis of autoimmune diseases. Here, we aimed to summarize the roles of lncRNAs as emerging novel biomarkers and therapeutic targets in SLE and RA. We conducted a narrative review summarizing original articles on lncRNAs associated with SLE and RA, published until November 1, 2021. Based on the studies on lncRNA expression profiles in samples (including PBMCs, serum, and exosomes), it was noted that most of the current research is focused on investigating the regulatory mechanisms of these lncRNAs in SLE and/or RA. Several lncRNAs have been hypothesized to play key roles in these diseases. In SLE, lncRNAs such as GAS5, NEAT1, TUG1, linc0949, and linc0597 are dysregulated and may serve as emerging novel biomarkers and therapeutic targets. In RA, many validated lncRNAs, such as HOTAIR, GAS5, and HIX003209, have been identified as promising novel biomarkers for both diagnosis and treatment. The shared lncRNAs, for example, GAS5, may participate in SLE pathogenesis through the mitogen-activated protein kinase pathway and trigger the AMP-activated protein kinase pathway in RA. Here, we summarize the data on key lncRNAs that may drive the pathogenesis of SLE and RA and could potentially serve as emerging novel biomarkers and therapeutic targets in the coming future.
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Affiliation(s)
- Han Wu
- Clinical Research Center, Department of Clinical Laboratory, Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Shuxian Chen
- Clinical Research Center, Department of Clinical Laboratory, Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Aifen Li
- Clinical Research Center, Department of Clinical Laboratory, Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Kangyuan Shen
- Clinical Research Center, Department of Clinical Laboratory, Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Shuting Wang
- Clinical Research Center, Department of Clinical Laboratory, Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Sijie Wang
- Clinical Research Center, Department of Clinical Laboratory, Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Ping Wu
- Clinical Research Center, Department of Clinical Laboratory, Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Wenying Luo
- Clinical Research Center, Department of Clinical Laboratory, Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Qingjun Pan
- Clinical Research Center, Department of Clinical Laboratory, Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
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Abstract
The last decade has seen an enormous increase in long non-coding RNA (lncRNA) research within rheumatology. LncRNAs are arbitrarily classed as non-protein encoding RNA transcripts that exceed 200 nucleotides in length. These transcripts have tissue and cell specific patterns of expression and are implicated in a variety of biological processes. Unsurprisingly, numerous lncRNAs are dysregulated in rheumatoid conditions, correlating with disease activity and cited as potential biomarkers and targets for therapeutic intervention. In this chapter, following an introduction into each condition, we discuss the lncRNAs involved in rheumatoid arthritis, osteoarthritis and systemic lupus erythematosus. These inflammatory joint conditions share several inflammatory signalling pathways and therefore not surprisingly many commonly dysregulated lncRNAs are shared across these conditions. In the interest of translational research only those lncRNAs which are strongly conserved have been addressed. The lncRNAs discussed here have diverse roles in regulating inflammation, proliferation, migration, invasion and apoptosis. Understanding the molecular basis of lncRNA function in rheumatology will be crucial in fully determining the inflammatory mechanisms that drive these conditions.
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Zhou X, Cao H, Wang M, Zou J, Wu W. Moderate-intensity treadmill running relieves motion-induced post-traumatic osteoarthritis mice by up-regulating the expression of lncRNA H19. Biomed Eng Online 2021; 20:111. [PMID: 34794451 PMCID: PMC8600697 DOI: 10.1186/s12938-021-00949-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 11/03/2021] [Indexed: 01/17/2023] Open
Abstract
BACKGROUND The purpose of this study was to explore whether moderate-intensity exercise can alleviate motion-induced post-traumatic osteoarthritis (PTOA) and the expression change of lncRNA H19 during this progression. METHODS Twenty-week-old male C57BL/6 mice were randomly divided into five groups: model control group (MC group, n = 6), treadmill model group (M group, n = 6), rehabilitation control group (RC group, n = 6), treadmill model + rehabilitation training group (M + R group, n = 6) and treadmill model + convalescent group (M + C group, n = 6). Paraffin sections were used to observe the pathological changes in the mouse knee joint in each group. A micro-CT was used to scan the knee joint to obtain the morphological indexes of the tibial plateau bone. Real-time PCR was used to detect the mRNA levels of inflammatory factors, synthetic and catabolic factors in cartilage. RESULTS After high-intensity exercise for 4 weeks, the inflammation and catabolism of the mouse knee cartilage were enhanced, and the anabolism was weakened. Further study showed that these results were partially reversed after 4-week moderate-intensity training. The results of hematoxylin-eosin staining confirmed this finding. Meanwhile, high-intensity exercise reduced the expression of lncRNA H19 in cartilage, while the expression of lncRNA H19 increased after 4 weeks of moderate-intensity exercise. CONCLUSION High-intensity treadmill running can cause injury to the knee cartilage in C57BL/6 mice which leads to PTOA and a decrease of lncRNA H19 expression in cartilage. Moderate-intensity exercise can relieve PTOA and partially reverse lncRNA H19 expression.
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Affiliation(s)
- Xuchang Zhou
- School of Kinesiology, Shanghai University of Sport, Shanghai, China
| | - Hong Cao
- School of Kinesiology, Shanghai University of Sport, Shanghai, China
| | - Miao Wang
- School of Kinesiology, Shanghai University of Sport, Shanghai, China
| | - Jun Zou
- School of Kinesiology, Shanghai University of Sport, Shanghai, China
| | - Wei Wu
- School of Kinesiology, Shanghai University of Sport, Shanghai, China.
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Shang H, Peng Q, Liu J, Liu Y, Long L. Screening and analysis for autophagy -related lncRNA in fibroblast -like synoviocytes from patients with rheumatoid arthritis. ZHONG NAN DA XUE XUE BAO. YI XUE BAN = JOURNAL OF CENTRAL SOUTH UNIVERSITY. MEDICAL SCIENCES 2021; 46:1071-1079. [PMID: 34911836 PMCID: PMC10930234 DOI: 10.11817/j.issn.1672-7347.2021.210374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Indexed: 11/03/2022]
Abstract
OBJECTIVES Long non-coding RNA (lncRNA) has become a key epigenetic regulator that regulates gene expression and affects a variety of biological processes. LncRNA plays an important role in the occurrence and development of rheumatoid arthritis (RA). The study on lncRNA in peripheral blood cells of RA patients has been reported. However, there is no study on autophagy regulation by lncRNA in RA patients. This study aims to provide a new direction for the diagnosis and treatment of RA via screening the changes of lncRNAs in RA fibroblast-like synoviocytes (RA-FLSs) before and after autophagy and finding the key lncRNAs targeting RA-FLSs autophagy. METHODS Synovial tissues of 6 RA patients after knee and hip joint surgery were obtained, and RA-FLSs were cultured to the 5th generation for further experiments (tissue culture method). After treatment with mTOR inhibitor PP242, the expression of LC3-II was detected by Western blotting. Total RNAs of 3 cases of RA-FLSs before and after treatment with mTOR inhibitor PP242 were extracted by TRIzol and screened by Agilent Human ceRNA Microarray 2019 (4×180 K, design ID: 086188) chip. The lncRNAs with significantly changed expression levels were selected (difference multiple≥2.0, P<0.05). Bioinformatics technology was used to analyze the gene ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway of the differentially expressed lncRNAs, and to explore the possible role of differentially expressed lncRNAs in the pathogenesis of RA. Subsequently, ENST00000584721.1 and ENST00000615939.1 were identified in all the 6 samples of RA-FLSs using real-time RT-PCR, which were selected by previous chip screen combined with GO enrichment analysis and KEGG analysis. RESULTS RA-FLSs were successfully isolated and cultured from the synovial tissues of the patient's knee or hip joint. After 6 RA-FLSs were treated with PP242, the expression level of autophagy marker protein LC3-II was increased (P<0.05). PP242 induced autophagy in RA-FLSs. LncRNA sequencing analysis showed that a total of 591 lncRNAs were significantly changed, of which 428 were up-regulated and 163 were down-regulated.Go analysis showed that these differentially expressed lncRNAs were associated with negative regulation of Th17 function, T cell related cytokines production, and TGF-β receptor signaling pathway, as well as IL-6 receptor complex formation and type I TGF-β receptor binding. KEGG analysis showed that autophagy pathway, TGF-β, TNF-α, IL-17 signaling pathway, and Th17, Th1, Th2, osteoclast differentiation pathway were the most abundant signal pathways of differentially expressed lncRNAs during autophagy. The expression of ENST00000584721.1 was up-regulated (P<0.05) and the expression ofENST00000615939.1 was down-regulated (P<0.05) in RA-FLSs undergoing autophagy, by using real-time RT-PCR validation which was in consistent with the microarray results. The reliability of microarray screening differential genes was confirmed. GO analysis showed that ENST00000584721.1 and ENST00000615939.1 were related to ribosome transport and autophagy assembly, respectively. KEGG analysis showed that ENST00000584721.1 was related to mitogen-activated protein kinase (MAPK) signaling pathway, and ENST00000615939.1 was related to FoxO signaling pathway. CONCLUSIONS Differentially expressed lncRNAs in RA-FLSs have been identified with microarray analysis. In RA, differential expression of lncRNAs is involved in the autophagy of RA-FLSs. The underlying mechanisms based on bioinformatics analysis include regulating the secretion of cytokines, such as IL-6, TGF-β, TNF-α and IL-17, participating in the immune cell differentiation, such as Th17, Th1, Th2 cells and osteoclasts, as well as regulating the autophagy pathway, MAPK, FoxO, and other signaling pathways. It has been verified that the expression of ENST0000584721.1 is up-regulated and ENST0000615939.1 is down-regulated after autophagy of RA FLSs, which provides a good experimental basis for further study on the mechanism of lncRNA in RA-FLSs autophagy.
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Affiliation(s)
- Hua Shang
- Zunyi Medical University, Zunyi Guizhou 563000.
- Department of Rheumatology and Immunology, Suining Central Hospital, Suining Sichuan 629000.
| | - Qing Peng
- Zunyi Medical University, Zunyi Guizhou 563000
| | - Jiajun Liu
- Zunyi Medical University, Zunyi Guizhou 563000
| | - Yan Liu
- Zunyi Medical University, Zunyi Guizhou 563000
| | - Li Long
- Zunyi Medical University, Zunyi Guizhou 563000.
- Department of Rheumatology and Immunology, Sichuan Provincial People's Hospital, Chengdu 610072, China.
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Liebold I, Grützkau A, Göckeritz A, Gerl V, Lindquist R, Feist E, Zänker M, Häupl T, Poddubnyy D, Zernicke J, Smiljanovic B, Alexander T, Burmester GR, Gay S, Stuhlmüller B. Peripheral blood mononuclear cells are hypomethylated in active rheumatoid arthritis and methylation correlates with disease activity. Rheumatology (Oxford) 2021; 60:1984-1995. [PMID: 33200208 DOI: 10.1093/rheumatology/keaa649] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 07/31/2020] [Indexed: 12/18/2022] Open
Abstract
OBJECTIVE Epigenetic modifications are dynamic and influence cellular disease activity. The aim of this study was to investigate global DNA methylation in peripheral blood mononuclear cells (PBMCs) of RA patients to clarify whether global DNA methylation pattern testing might be useful in monitoring disease activity as well as the response to therapeutics. METHODS Flow cytometric measurement of 5-methyl-cytosine (5'-mC) was established using the cell line U937. In the subsequent prospective study, 62 blood samples were investigated, including 17 healthy donors and 45 RA patients at baseline and after 3 months of treatment with methotrexate, the IL-6 receptor inhibitor sarilumab, and Janus kinase inhibitors. Methylation status was assessed with an anti-5'-mC antibody and analysed in PBMCs and CD4+, CD8+, CD14+ and CD19+ subsets. Signal intensities of 5'-mC were correlated with 28-joint DASs with ESR and CRP (DAS28-ESR and DAS28-CRP). RESULTS Compared with healthy individuals, PBMCs of RA patients showed a significant global DNA hypomethylation. Signal intensities of 5'-mC correlated with transcription levels of DNMT1, DNMT3B and MTR genes involved in methylation processes. Using flow cytometry, significant good correlations and linear regression values were achieved in RA patients between global methylation levels and DAS28-ESR values for PBMCs (r = -0.55, P = 0.002), lymphocytes (r = -0.57, P = 0.001), CD4+ (r = -0.57, P = 0.001), CD8+ (r = -0.54, P = 0.001), CD14+ (r = -0.49, P = 0.008) and CD19+ (r = -0.52, P = 0.004) cells. CONCLUSIONS The degree of global DNA methylation was found to be associated with disease activity. Based on this novel approach, the degree of global methylation is a promising biomarker for therapy monitoring and the prediction of therapy outcome in inflammatory diseases.
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Affiliation(s)
- Ilka Liebold
- Division of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Institute of Health, Freie Universität and Humboldt-Universität, Berlin, Germany
| | - Andreas Grützkau
- Deutsches Rheuma-Forschungszentrum Berlin (DRFZ), a Leibniz-Institute, Berlin, Germany
| | - Anika Göckeritz
- Division of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Institute of Health, Freie Universität and Humboldt-Universität, Berlin, Germany
| | - Velia Gerl
- Division of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Institute of Health, Freie Universität and Humboldt-Universität, Berlin, Germany
| | - Randall Lindquist
- Deutsches Rheuma-Forschungszentrum Berlin (DRFZ), a Leibniz-Institute, Berlin, Germany
| | - Eugen Feist
- Division of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Institute of Health, Freie Universität and Humboldt-Universität, Berlin, Germany.,Department of Rheumatology, Helios Fachklinik, Vogelsang-Gommern, Germany
| | - Michael Zänker
- Immanuel Klinikum Bernau Herzzentrum Brandenburg, Medizinische Hochschule Brandenburg, Bernau, Germany
| | - Thomas Häupl
- Division of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Institute of Health, Freie Universität and Humboldt-Universität, Berlin, Germany
| | - Denis Poddubnyy
- Division of Gastroenterology, Infectious Diseases and Rheumatology, Charité - Universitätsmedizin Berlin, Corporate Member of Berlin Institute of Health, Freie Universität and Humboldt-Universität, Berlin, Germany
| | - Jan Zernicke
- Division of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Institute of Health, Freie Universität and Humboldt-Universität, Berlin, Germany
| | - Biljana Smiljanovic
- Division of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Institute of Health, Freie Universität and Humboldt-Universität, Berlin, Germany
| | - Tobias Alexander
- Division of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Institute of Health, Freie Universität and Humboldt-Universität, Berlin, Germany
| | - Gerd R Burmester
- Division of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Institute of Health, Freie Universität and Humboldt-Universität, Berlin, Germany
| | - Steffen Gay
- Center of Experimental Rheumatology, University Hospital Zurich, Zurich, Switzerland
| | - Bruno Stuhlmüller
- Division of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Institute of Health, Freie Universität and Humboldt-Universität, Berlin, Germany
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Tian X, Wang Y, Lu Y, Wang W, Du J, Chen S, Zhou H, Cai W, Xiao Y. Conditional depletion of macrophages ameliorates cholestatic liver injury and fibrosis via lncRNA-H19. Cell Death Dis 2021; 12:646. [PMID: 34168124 PMCID: PMC8225916 DOI: 10.1038/s41419-021-03931-1] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 06/10/2021] [Accepted: 06/11/2021] [Indexed: 12/13/2022]
Abstract
Although macrophages are recognized as important players in the pathogenesis of chronic liver diseases, their roles in cholestatic liver fibrosis remain incompletely understood. We previously reported that long noncoding RNA-H19 (lncRNA-H19) contributes to cholangiocyte proliferation and cholestatic liver fibrosis of biliary atresia (BA). We here show that monocyte/macrophage CD11B mRNA levels are increased significantly in livers of BA patients and positively correlated with the progression of liver inflammation and fibrosis. The macrophages increasingly infiltrate and accumulate in the fibrotic niche and peribiliary areas in livers of BA patients. Selective depletion of macrophages using the transgenic CD11b-diphtheria toxin receptor (CD11b-DTR) mice halts bile duct ligation (BDL)-induced progression of liver damage and fibrosis. Meanwhile, macrophage depletion significantly reduces the BDL-induced hepatic lncRNA-H19. Overexpression of H19 in livers using adeno-associated virus serotype 9 (AAV9) counteracts the effects of macrophage depletion on liver fibrosis and cholangiocyte proliferation. Additionally, both H19 knockout (H19-/-) and conditional deletion of H19 in macrophage (H19ΔCD11B) significantly depress the macrophage polarization and recruitment. lncRNA-H19 overexpressed in THP-1 macrophages enhance expression of Rho-GTPase CDC42 and RhoA. In conclusions, selectively depletion of macrophages suppresses cholestatic liver injuries and fibrosis via the lncRNA-H19 and represents a potential therapeutic strategy for rapid liver fibrosis in BA patients.
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MESH Headings
- Animals
- CD11b Antigen/genetics
- CD11b Antigen/metabolism
- Case-Control Studies
- Cell Proliferation
- Cholestasis/complications
- Heparin-binding EGF-like Growth Factor/genetics
- Heparin-binding EGF-like Growth Factor/metabolism
- Humans
- Liver/metabolism
- Liver/pathology
- Liver Cirrhosis, Biliary/genetics
- Liver Cirrhosis, Biliary/metabolism
- Liver Cirrhosis, Biliary/pathology
- Liver Cirrhosis, Biliary/prevention & control
- Liver Cirrhosis, Experimental/genetics
- Liver Cirrhosis, Experimental/metabolism
- Liver Cirrhosis, Experimental/pathology
- Liver Cirrhosis, Experimental/prevention & control
- Macrophage Activation
- Macrophages/metabolism
- Macrophages/pathology
- Mice, Inbred C57BL
- Mice, Knockout
- RNA, Long Noncoding/genetics
- RNA, Long Noncoding/metabolism
- THP-1 Cells
- cdc42 GTP-Binding Protein/genetics
- cdc42 GTP-Binding Protein/metabolism
- rhoA GTP-Binding Protein/genetics
- rhoA GTP-Binding Protein/metabolism
- Mice
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Affiliation(s)
- Xinbei Tian
- Division of Pediatric Gastroenterology and Nutrition, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Ying Wang
- Division of Pediatric Gastroenterology and Nutrition, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Ying Lu
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
- Shanghai Institute of Pediatric Research, Shanghai, China
| | - Weipeng Wang
- Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jun Du
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
- Shanghai Institute of Pediatric Research, Shanghai, China
| | - Shanshan Chen
- Division of Pediatric Gastroenterology and Nutrition, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Huiping Zhou
- Department of Microbiology and Immunology and McGuire Veterans AfSfairs Medical Center, Virginia Commonwealth University, Richmond, VA, USA
| | - Wei Cai
- Division of Pediatric Gastroenterology and Nutrition, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China.
- Shanghai Institute of Pediatric Research, Shanghai, China.
- Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
| | - Yongtao Xiao
- Division of Pediatric Gastroenterology and Nutrition, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China.
- Shanghai Institute of Pediatric Research, Shanghai, China.
- Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
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Wijesinghe SN, Nicholson T, Tsintzas K, Jones SW. Involvements of long noncoding RNAs in obesity-associated inflammatory diseases. Obes Rev 2021; 22:e13156. [PMID: 33078547 DOI: 10.1111/obr.13156] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 09/24/2020] [Accepted: 09/25/2020] [Indexed: 12/15/2022]
Abstract
Obesity is associated with chronic low-grade inflammation that affects the phenotype of multiple tissues and therefore is implicated in the development and progression of several age-related chronic inflammatory disorders. Importantly, a new family of noncoding RNAs, termed long noncoding RNAs (lncRNAs), have been identified as key regulators of inflammatory signalling pathways that can mediate both pretranscriptional and posttranscriptional gene regulation. Furthermore, several lncRNAs have been identified, which are differentially expressed in multiple tissue types in individuals who are obese or in preclinical models of obesity. In this review, we examine the evidence for the role of several of the most well-studied lncRNAs in the regulation of inflammatory pathways associated with obesity. We highlight the evidence for their differential expression in the obese state and in age-related conditions including insulin resistance, type 2 diabetes (T2D), sarcopenia, osteoarthritis and rheumatoid arthritis, where obesity plays a significant role. Determining the expression and functional role of lncRNAs in mediating obesity-associated chronic inflammation will advance our understanding of the epigenetic regulatory pathways that underlie age-related inflammatory diseases and may also ultimately identify new targets for therapeutic intervention.
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Affiliation(s)
- Susanne N Wijesinghe
- Institute of Inflammation and Ageing, MRC Versus Arthritis Centre for Musculoskeletal Ageing Research, University of Birmingham, Birmingham, UK
| | - Thomas Nicholson
- Institute of Inflammation and Ageing, MRC Versus Arthritis Centre for Musculoskeletal Ageing Research, University of Birmingham, Birmingham, UK
| | - Kostas Tsintzas
- MRC Versus Arthritis Centre for Musculoskeletal Ageing Research, School of Life Sciences, University of Nottingham, Nottingham, UK
| | - Simon W Jones
- Institute of Inflammation and Ageing, MRC Versus Arthritis Centre for Musculoskeletal Ageing Research, University of Birmingham, Birmingham, UK
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Miao C, Bai L, Yang Y, Huang J. Dysregulation of lncRNAs in Rheumatoid Arthritis: Biomarkers, Pathogenesis and Potential Therapeutic Targets. Front Pharmacol 2021; 12:652751. [PMID: 33776780 PMCID: PMC7994855 DOI: 10.3389/fphar.2021.652751] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Accepted: 02/05/2021] [Indexed: 12/15/2022] Open
Abstract
Rheumatoid arthritis (RA) is a chronic autoimmune disease of unknown etiology, mainly manifested by persistent abnormal proliferation of fibroblast-like synoviocytes (FLSs), inflammation, synovial hyperplasia and cartilage erosion, accompanied by joint swelling and joint destruction. Abnormal expression or function of long noncoding RNAs (lncRNAs) are closely related to human diseases, including cancers, mental diseases, autoimmune diseases and others. The abnormal sequence and spatial structure of lncRNAs, the disorder expression and the abnormal interaction with the binding protein will lead to the change of gene expression in the way of epigenetic modification. Increasing evidence demonstrated that lncRNAs were involved in the activation of FLSs, which played a key role in the pathogenesis of RA. In this review, the research progress of lncRNAs in the pathogenesis of RA was systematically summarized, including the role of lncRNAs in the diagnosis of RA, the regulatory mechanism of lncRNAs in the pathogenesis of RA, and the intervention role of lncRNAs in the treatment of RA. Furthermore, the activated signal pathways, the role of DNA methylation and other mechanism have also been overview in this review.
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Affiliation(s)
- Chenggui Miao
- Department of Pharmacology, School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, China.,Anhui Provincial Key Laboratory of Chinese Medicine Compound, Anhui University of Chinese Medicine, Hefei, China.,Department of Pharmacy, School of Life and Health Sciences, Anhui University of Science and Technology, Fengyang, China
| | - Liangliang Bai
- Department of Biomedical Engineering, School of Biomedical Engineering, Anhui Medical University, Hefei, China
| | - Yaru Yang
- Department of Pharmacy, First Affiliated Hospital, Anhui Medical University, Hefei, China
| | - Jinling Huang
- Department of Pharmacology, School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, China
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31
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Zhu X, Zhu Y, Ding C, Zhang W, Guan H, Li C, Lin X, Zhang Y, Huang C, Zhang L, Yu X, Zhang X, Zhu W. LncRNA H19 regulates macrophage polarization and promotes Freund's complete adjuvant-induced arthritis by upregulating KDM6A. Int Immunopharmacol 2021; 93:107402. [PMID: 33540246 DOI: 10.1016/j.intimp.2021.107402] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 12/27/2020] [Accepted: 01/12/2021] [Indexed: 12/27/2022]
Abstract
Aberrant expression of long non-coding RNA (lncRNA) H19 is tightly linked to multiple steps of tumorigenesis via the modulation of cell proliferation and apoptosis; however, the pathological significance and regulatory mechanisms of lncRNA H19 in macrophages remain obscure. To investigate whether lncRNA H19 modulates macrophage activation in rheumatoid arthritis (RA), lncRNA H19 levels in PMA-induced PBMC from patients with RA and healthy volunteers were assessed. In addition, the distribution of macrophage subsets, macrophage phenotypic characteristics, and pro-inflammatory gene expression were examined in lncRNA H19 smart silencer- or pcDNA 3.1- H19-transfected macrophages and AAV8-mediated H19 overexpression in a Freund' s complete adjuvant-induced arthritis mouse model. The level of lncRNA H19 was higher in RA patients than in healthy volunteers. Silencing of lncRNA H19 altered lipopolysaccharide plus interferon-induced M1 macrophage polarization and decreased IL-6, CD80, CCL8, and CXCL10 expression in macrophages of RA patients. LncRNA H19 overexpression markedly induced IL-6, CD80, HLA-DR, KDM6A, STAT1, IRF5, CCL8, CXCL9, CXCL10, and CXCL11 expression in macrophages and promoted macrophage migration. AAV8-mediated H19 overexpression aggravated arthritis in mice by promoting M1 macrophage polarization along with iNOS, IL-6, CCL8, CXCL9, CXCL10, CXCL11, MMP3, MMP13 and COX-2 expression in mononuclear cells isolated from the swollen ankle. GSK-J4, an inhibitor of KDM6A, suppressed the activity of lncRNA H19 in macrophages and ameliorated lncRNA H19-aggravated arthritis. In summary, the current study demonstrated that lncRNA H19 is upregulated in RA patients and arthritic mice. LncRNA H19 promotes M1 macrophage polarization and aggravates arthritis by upregulating KDM6A expression.
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Affiliation(s)
- Xiaodong Zhu
- Department of Immunology, Mudanjiang Medical University, Mudanjiang, Heilongjiang 157011, China
| | - Ye Zhu
- Department of Obstetrics and Gynecology, Peking University People's Hospital, Beijing 100044, China
| | - Chen Ding
- Department of Immunology, Mudanjiang Medical University, Mudanjiang, Heilongjiang 157011, China
| | - Weiting Zhang
- Department of Rheumatology, Hongqi Hospital of Mudanjiang Medical University, Mudanjiang, Heilongjiang 157011, China
| | - Huilin Guan
- Department of Immunology, Mudanjiang Medical University, Mudanjiang, Heilongjiang 157011, China
| | - Chunmei Li
- Department of Immunology, Mudanjiang Medical University, Mudanjiang, Heilongjiang 157011, China
| | - Xiao Lin
- Department of Immunology, Mudanjiang Medical University, Mudanjiang, Heilongjiang 157011, China
| | - Yang Zhang
- Department of Immunology, Mudanjiang Medical University, Mudanjiang, Heilongjiang 157011, China
| | - Chunyan Huang
- Department of Immunology, Mudanjiang Medical University, Mudanjiang, Heilongjiang 157011, China
| | - Luyao Zhang
- Department of Immunology, Mudanjiang Medical University, Mudanjiang, Heilongjiang 157011, China
| | - Xin Yu
- Department of Immunology, Mudanjiang Medical University, Mudanjiang, Heilongjiang 157011, China
| | - Xiaomin Zhang
- Department of Rheumatology, Hongqi Hospital of Mudanjiang Medical University, Mudanjiang, Heilongjiang 157011, China
| | - Wei Zhu
- Department of Immunology, Mudanjiang Medical University, Mudanjiang, Heilongjiang 157011, China.
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Li D, Yang C, Yin C, Zhao F, Chen Z, Tian Y, Dang K, Jiang S, Zhang W, Zhang G, Qian A. LncRNA, Important Player in Bone Development and Disease. Endocr Metab Immune Disord Drug Targets 2020; 20:50-66. [PMID: 31483238 DOI: 10.2174/1871530319666190904161707] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Revised: 07/26/2019] [Accepted: 08/20/2019] [Indexed: 02/08/2023]
Abstract
BACKGROUND Bone is an important tissue and its normal function requires tight coordination of transcriptional networks and signaling pathways, and many of these networks/ pathways are dysregulated in pathological conditions affecting cartilage and bones. Long non-coding RNA (lncRNA) refers to a class of RNAs with a length of more than 200 nucleotides, lack of protein-coding potential, and exhibiting a wide range of biological functions. Although studies on lcnRNAs are still in their infancy, they have emerged as critical players in bone biology and bone diseases. The functions and exact mechanism of bone-related lncRNAs have not been fully classified yet. OBJECTIVE The objective of this article is to summarize the current literature on lncRNAs on the basis of their role in bone biology and diseases, focusing on their emerging molecular mechanism, pathological implications and therapeutic potential. DISCUSSION A number of lncRNAs have been identified and shown to play important roles in multiple bone cells and bone disease. The function and mechanism of bone-related lncRNA remain to be elucidated. CONCLUSION At present, majority of knowledge is limited to cellular levels and less is known on how lncRNAs could potentially control the development and homeostasis of bone. In the present review, we highlight some lncRNAs in the field of bone biology and bone disease. We also delineate some lncRNAs that might have deep impacts on understanding bone diseases and providing new therapeutic strategies to treat these diseases.
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Affiliation(s)
- Dijie Li
- Lab for Bone Metabolism, Key Lab for Space Biosciences and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China.,Research Center for Special Medicine and Health Systems Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China.,NPU-UAB Joint Laboratory for Bone Metabolism, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China
| | - Chaofei Yang
- Lab for Bone Metabolism, Key Lab for Space Biosciences and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China.,Research Center for Special Medicine and Health Systems Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China.,NPU-UAB Joint Laboratory for Bone Metabolism, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China
| | - Chong Yin
- Lab for Bone Metabolism, Key Lab for Space Biosciences and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China.,Research Center for Special Medicine and Health Systems Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China.,NPU-UAB Joint Laboratory for Bone Metabolism, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China
| | - Fan Zhao
- Lab for Bone Metabolism, Key Lab for Space Biosciences and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China.,Research Center for Special Medicine and Health Systems Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China.,NPU-UAB Joint Laboratory for Bone Metabolism, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China
| | - Zhihao Chen
- Lab for Bone Metabolism, Key Lab for Space Biosciences and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China.,Research Center for Special Medicine and Health Systems Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China.,NPU-UAB Joint Laboratory for Bone Metabolism, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China
| | - Ye Tian
- Lab for Bone Metabolism, Key Lab for Space Biosciences and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China.,Research Center for Special Medicine and Health Systems Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China.,NPU-UAB Joint Laboratory for Bone Metabolism, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China
| | - Kai Dang
- Lab for Bone Metabolism, Key Lab for Space Biosciences and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China.,Research Center for Special Medicine and Health Systems Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China.,NPU-UAB Joint Laboratory for Bone Metabolism, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China
| | - Shanfeng Jiang
- Lab for Bone Metabolism, Key Lab for Space Biosciences and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China.,Research Center for Special Medicine and Health Systems Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China.,NPU-UAB Joint Laboratory for Bone Metabolism, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China
| | - Wenjuan Zhang
- Lab for Bone Metabolism, Key Lab for Space Biosciences and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China.,Research Center for Special Medicine and Health Systems Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China.,NPU-UAB Joint Laboratory for Bone Metabolism, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China
| | - Ge Zhang
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, SAR, China.,Institute of Integrated Bioinfomedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, SAR, China
| | - Airong Qian
- Lab for Bone Metabolism, Key Lab for Space Biosciences and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China.,Research Center for Special Medicine and Health Systems Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China.,NPU-UAB Joint Laboratory for Bone Metabolism, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China
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Wang B, Suen CW, Ma H, Wang Y, Kong L, Qin D, Lee YWW, Li G. The Roles of H19 in Regulating Inflammation and Aging. Front Immunol 2020; 11:579687. [PMID: 33193379 PMCID: PMC7653221 DOI: 10.3389/fimmu.2020.579687] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Accepted: 10/05/2020] [Indexed: 12/17/2022] Open
Abstract
Accumulating evidence suggests that long non-coding RNA H19 correlates with several aging processes. However, the role of H19 in aging remains unclear. Many studies have elucidated a close connection between H19 and inflammatory genes. Chronic systemic inflammation is an established factor associated with various diseases during aging. Thus, H19 might participate in the development of age-related diseases by interplay with inflammation and therefore provide a protective function against age-related diseases. We investigated the inflammatory gene network of H19 to understand its regulatory mechanisms. H19 usually controls gene expression by acting as a microRNA sponge, or through mir-675, or by leading various protein complexes to genes at the chromosome level. The regulatory gene network has been intensively studied, whereas the biogenesis of H19 remains largely unknown. This literature review found that the epithelial-mesenchymal transition (EMT) and an imprinting gene network (IGN) might link H19 with inflammation. Evidence indicates that EMT and IGN are also tightly controlled by environmental stress. We propose that H19 is a stress-induced long non-coding RNA. Because environmental stress is a recognized age-related factor, inflammation and H19 might serve as a therapeutic axis to fight against age-related diseases.
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Affiliation(s)
- Bin Wang
- The Chinese University of Hong Kong (CUHK)-Guangzhou Regenerative Medicine and Health Guangdong Laboratory (GDL), Advanced Institute for Regenerative MedicineBioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, China.,Innovation Center for Translational Medicine, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Chun Wai Suen
- Department of Haematology, University of Cambridge, Cambridge, United Kingdom
| | - Haibin Ma
- The Chinese University of Hong Kong (CUHK)-Guangzhou Regenerative Medicine and Health Guangdong Laboratory (GDL), Advanced Institute for Regenerative MedicineBioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, China
| | - Yan Wang
- Innovation Center for Translational Medicine, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Ling Kong
- The Chinese University of Hong Kong (CUHK)-Guangzhou Regenerative Medicine and Health Guangdong Laboratory (GDL), Advanced Institute for Regenerative MedicineBioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, China
| | - Dajiang Qin
- The Chinese University of Hong Kong (CUHK)-Guangzhou Regenerative Medicine and Health Guangdong Laboratory (GDL), Advanced Institute for Regenerative MedicineBioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, China.,Innovation Center for Translational Medicine, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Yuk Wai Wayne Lee
- Department of Orthopaedics & Traumatology, Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China
| | - Gang Li
- The Chinese University of Hong Kong (CUHK)-Guangzhou Regenerative Medicine and Health Guangdong Laboratory (GDL), Advanced Institute for Regenerative MedicineBioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, China.,Department of Orthopaedics & Traumatology, Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China.,Ministry of Education Key Laboratory for Regenerative Medicine, School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China.,Innovation Center for Translational Medicine, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
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Wan X, Tian X, Du J, Lu Y, Xiao Y. Long non-coding RNA H19 deficiency ameliorates bleomycin-induced pulmonary inflammation and fibrosis. Respir Res 2020; 21:290. [PMID: 33138822 PMCID: PMC7607673 DOI: 10.1186/s12931-020-01534-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Accepted: 10/05/2020] [Indexed: 12/11/2022] Open
Abstract
Background The poor understanding of pathogenesis in idiopathic pulmonary fibrosis (IPF) impaired development of effective therapeutic strategies. The aim of the current study is to investigate the roles of long non-coding RNA H19 (lncRNA H19) in the pulmonary inflammation and fibrosis of IPF. Methods Bleomycin was used to induce pulmonary inflammation and fibrosis in mice. The mRNAs and proteins expression in lung tissues was determined by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. H19 knockout (H19−/−) mice were generated by CRISPR/Cas9. Results The expression of H19 mRNA was up-regulated in fibrotic lungs patients with IPF as well as in lungs tissues that obtained from bleomycin-treated mice. H19−/− mice suppressed bleomycin-mediated pulmonary inflammation and inhibited the Il6/Stat3 signaling. H19 deficiency ameliorated bleomycin-induced pulmonary fibrosis and repressed the activation of TGF-β/Smad and S1pr2/Sphk2 in the lungs of bleomycin-treated mice. Conclusions Our data suggests that H19 is a profibrotic lncRNA and a potential therapeutic target for IPF.
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Affiliation(s)
- Xiaoyu Wan
- Department of Respiratory Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xinbei Tian
- Shanghai Institute for Pediatric Research, Shanghai, China
| | - Jun Du
- Shanghai Institute for Pediatric Research, Shanghai, China
| | - Ying Lu
- Shanghai Institute for Pediatric Research, Shanghai, China
| | - Yongtao Xiao
- Shanghai Institute for Pediatric Research, Shanghai, China. .,Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, No. 1665, Kong Jiang Road, Shanghai, China.
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35
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Chatterjee S, Bhattcharjee D, Misra S, Saha A, Bhattacharyya NP, Ghosh A. Increase in MEG3, MALAT1, NEAT1 significantly predicts the clinical parameters in patients with rheumatoid arthritis. Per Med 2020; 17:445-457. [PMID: 33026292 DOI: 10.2217/pme-2020-0009] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Aim: This study investigated deregulation of lncRNAs MEG3, MALAT1, NEAT1 and their associations with clinical parameters in rheumatoid arthritis (RA). Materials & methods: LncRNAs MALAT1, MEG3, NEAT1 were quantified from peripheral blood mono-nuclear cells (PBMCs) and plasma of 82 RA patients with 15 matched controls and from knee fluid of 24 RA patients with ten osteoarthritis controls. Multivariate analyses were performed among lncRNAs and clinical parameters of RA. Results: MALAT1, MEG3, NEAT1 were increased in PBMCs, plasma, synovial fluid (p < 0.05) of RA patients. Significant correlations were observed for MEG3 with TJC (r = 0.29), NEAT1 with TJC (r = 0.49), swollen joint count (r = 0.20), DAS28-CRP (r = 0.29). Multivariate analysis revealed that 48.5% of TJC and 31.5% of swollen joint count could be predicted by lncRNAs. Conclusion: The findings suggested that the lncRNAs might be explored as probable markers in monitoring disease activity.
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Affiliation(s)
- Sudipta Chatterjee
- Department of Clinical Immunology & Rheumatology, Institute of Postgraduate Medical Education & Research, Kolkata, West Bengal
| | - Dipanjan Bhattcharjee
- Department of Clinical Immunology & Rheumatology, Institute of Postgraduate Medical Education & Research, Kolkata, West Bengal
| | - Sanchaita Misra
- Department of Clinical Immunology & Rheumatology, Institute of Postgraduate Medical Education & Research, Kolkata, West Bengal
| | - Ayindrila Saha
- Department of Clinical Immunology & Rheumatology, Institute of Postgraduate Medical Education & Research, Kolkata, West Bengal
| | - Nitai Pada Bhattacharyya
- (Retired professor) Crystallography & Molecular Biology Division, Saha Institute of Nuclear Physics, Kolkata, West Bengal
| | - Alakendu Ghosh
- Department of Clinical Immunology & Rheumatology, Institute of Postgraduate Medical Education & Research, Kolkata, West Bengal
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Zahid KR, Raza U, Chen J, Raj UJ, Gou D. Pathobiology of pulmonary artery hypertension: role of long non-coding RNAs. Cardiovasc Res 2020; 116:1937-1947. [PMID: 32109276 DOI: 10.1093/cvr/cvaa050] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Revised: 11/30/2019] [Accepted: 02/25/2020] [Indexed: 12/30/2022] Open
Abstract
Pulmonary arterial hypertension (PAH) is a disease with complex pathobiology, significant morbidity and mortality, and remains without a cure. It is characterized by vascular remodelling associated with uncontrolled proliferation of pulmonary artery smooth muscle cells, endothelial cell proliferation and dysfunction, and endothelial-to-mesenchymal transition, leading to narrowing of the vascular lumen, increased vascular resistance and pulmonary arterial pressure, which inevitably results in right heart failure and death. There are multiple molecules and signalling pathways that are involved in the vascular remodelling, including non-coding RNAs, i.e. microRNAs and long non-coding RNAs (lncRNAs). It is only in recent years that the role of lncRNAs in the pathobiology of pulmonary vascular remodelling and right ventricular dysfunction is being vigorously investigated. In this review, we have summarized the current state of knowledge about the role of lncRNAs as key drivers and gatekeepers in regulating major cellular and molecular trafficking involved in the pathogenesis of PAH. In addition, we have discussed the limitations and challenges in translating lncRNA research in vivo and in therapeutic applications of lncRNAs in PAH.
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MESH Headings
- Animals
- Arterial Pressure
- Cell Proliferation
- Endothelial Cells/metabolism
- Endothelial Cells/pathology
- Endothelium, Vascular/metabolism
- Endothelium, Vascular/pathology
- Endothelium, Vascular/physiopathology
- Epithelial-Mesenchymal Transition
- Gene Expression Regulation
- Humans
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/pathology
- Muscle, Smooth, Vascular/physiopathology
- Myocytes, Smooth Muscle/metabolism
- Myocytes, Smooth Muscle/pathology
- Pulmonary Arterial Hypertension/genetics
- Pulmonary Arterial Hypertension/metabolism
- Pulmonary Arterial Hypertension/pathology
- Pulmonary Arterial Hypertension/physiopathology
- Pulmonary Artery/metabolism
- Pulmonary Artery/pathology
- Pulmonary Artery/physiopathology
- RNA, Long Noncoding/genetics
- RNA, Long Noncoding/metabolism
- Signal Transduction
- Vascular Remodeling
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Affiliation(s)
- Kashif Rafiq Zahid
- Shenzhen Key Laboratory of Microbial Genetic Engineering, Vascular Disease Research Center, College of Life Sciences and Oceanography, Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Carson International Cancer Center, Shenzhen University, Nanhai Road, Shenzhen, Guangdong 518060, China
- Key Laboratory of Optoelectronic Devices, Systems of Ministry of Education and Guangdong Province, College of Optoelectronic Engineering, Shenzhen University, Shenzhen, Guangdong 518060, China
| | - Umar Raza
- Department of Biological Sciences, National University of Medical Sciences (NUMS), Khadim Abid Majeed Road, Rawalpindi, Pakistan
| | - Jidong Chen
- Shenzhen Key Laboratory of Microbial Genetic Engineering, Vascular Disease Research Center, College of Life Sciences and Oceanography, Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Carson International Cancer Center, Shenzhen University, Nanhai Road, Shenzhen, Guangdong 518060, China
| | - Usha J Raj
- Department of Pediatrics, University of Illinois at Chicago, Chicago, IL, USA
| | - Deming Gou
- Shenzhen Key Laboratory of Microbial Genetic Engineering, Vascular Disease Research Center, College of Life Sciences and Oceanography, Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Carson International Cancer Center, Shenzhen University, Nanhai Road, Shenzhen, Guangdong 518060, China
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Taheri M, Eghtedarian R, Dinger ME, Ghafouri-Fard S. Dysregulation of non-coding RNAs in Rheumatoid arthritis. Biomed Pharmacother 2020; 130:110617. [DOI: 10.1016/j.biopha.2020.110617] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 07/26/2020] [Accepted: 08/02/2020] [Indexed: 02/07/2023] Open
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Fu X, Song G, Ni R, Liu H, Xu Z, Zhang D, He F, Huang G. LncRNA-H19 silencing suppresses synoviocytes proliferation and attenuates collagen-induced arthritis progression by modulating miR-124a. Rheumatology (Oxford) 2020; 60:430-440. [DOI: 10.1093/rheumatology/keaa395] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Revised: 06/08/2020] [Indexed: 12/14/2022] Open
Abstract
Abstract
Objectives
Long non-coding RNA H19 (lncRNA-H19) is highly expressed in fibroblast-like synoviocytes (FLS) from patients with RA. The present study aimed to clarify the pathological significance and regulatory mechanisms of lncRNA-H19 in FLS.
Methods
Mice with CIA were locally injected with LV-shH19. The progression of CIA was explored by measuring arthritic index (AI), paw thickness (PT) and histologic analysis. The growth and cell cycle of human synoviocyte MH7A were assessed by CCK-8 and flow cytometric analysis. The putative binding sites between lncRNA-H19 and miR-124a were predicted online, and the binding was identified by luciferase assay. RT-qPCR, Western blot and luciferase assay were performed to explore the molecular mechanisms between liver X receptor (LXR), lncRNA-H19, miR-124a and its target genes.
Results
The expression of lncRNA-H19 was closely associated with the proliferation of synoviocytes and knockdown of lncRNA-H19 significantly ameliorated the progression of CIA, reflected by decreased AI, PT and cartilage destruction. Notably, lncRNA-H19 competitively bound to miR-124a, which directly targets CDK2 and MCP-1. It was confirmed that lncRNA-H19 regulates the proliferation of synoviocytes by acting as a sponge of miR-124a to modulate CDK2 and MCP-1 expression. Furthermore, the agonists of LXR inhibited lncRNA-H19-mediated miR-124a-CDK2/MCP-1 signalling pathway in synoviocytes. The ‘lncRNA-H19-miR-124a-CDK2/MCP-1’ axis plays an important role in LXR anti-arthritis.
Conclusion
Regulation of the miR-124a-CDK2/MCP-1 pathway by lncRNA-H19 plays a crucial role in the proliferation of FLS. Targeting this axis has therapeutic potential in the treatment of RA and may represent a novel strategy for RA treatment.
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Affiliation(s)
- Xiaohong Fu
- Department of Biochemistry and Molecular Biology, College of Basic Medical Science
| | - Guojing Song
- Department of Biochemistry and Molecular Biology, College of Basic Medical Science
| | - Rongrong Ni
- Department of Biochemistry and Molecular Biology, College of Basic Medical Science
| | - Han Liu
- Department of Emergency, Southwest Hospital
| | - Zhizhen Xu
- Department of Biochemistry and Molecular Biology, College of Basic Medical Science
| | - Dinglin Zhang
- Department of Chemistry, College of Basic Medical Science, Third Military Medical University (Army Medical University), Chongqing, China
| | - Fengtian He
- Department of Biochemistry and Molecular Biology, College of Basic Medical Science
| | - Gang Huang
- Department of Biochemistry and Molecular Biology, College of Basic Medical Science
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39
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Sikora M, Marycz K, Smieszek A. Small and Long Non-coding RNAs as Functional Regulators of Bone Homeostasis, Acting Alone or Cooperatively. MOLECULAR THERAPY. NUCLEIC ACIDS 2020; 21:792-803. [PMID: 32791451 PMCID: PMC7419272 DOI: 10.1016/j.omtn.2020.07.017] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 05/15/2020] [Accepted: 07/10/2020] [Indexed: 12/16/2022]
Abstract
Emerging knowledge indicates that non-coding RNAs, including microRNAs (miRNAs) and long-noncoding RNAs (lncRNAs), have a pivotal role in bone development and the pathogenesis of bone-related disorders. Most recently, miRNAs have started to be regarded as potential biomarkers or targets for various sets of diseases, while lncRNAs have gained attention as a new layer of gene expression control acting through versatile interactions, also with miRNAs. The rapid development of RNA sequencing techniques based on next-generation sequencing (NGS) gives us better insight into molecular pathways regulated by the miRNA-lncRNA network. In this review, we summarize the current knowledge related to the function of miRNAs and lncRNAs as regulators of genes that are crucial for proper bone metabolism and homeostasis. We have characterized important non-coding RNAs and their expression signatures, in relationship to bone. Analysis of the biological function of miRNAs and lncRNAs, as well as their network, will pave the way for a better understanding of the pathogenesis of various bone disorders. We also think that this knowledge may lead to the development of innovative diagnostic tools and therapeutic approaches for bone-related disorders.
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Affiliation(s)
- Mateusz Sikora
- Department of Experimental Biology, Faculty of Biology and Animal Science, University of Environmental and Life Sciences Wroclaw, Norwida 27B Street, 50-375 Wroclaw, Poland
| | - Krzysztof Marycz
- International Institute of Translational Medicine, Jesionowa 11 Street, 55-124 Malin, Poland; Collegium Medicum, Institute of Medical Science, Cardinal Stefan Wyszynski University (UKSW), Wóycickiego 1/3, 01-938 Warsaw, Poland
| | - Agnieszka Smieszek
- Department of Experimental Biology, Faculty of Biology and Animal Science, University of Environmental and Life Sciences Wroclaw, Norwida 27B Street, 50-375 Wroclaw, Poland.
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40
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Discrepancy between Jun/Fos Proto-Oncogene mRNA and Protein Expression in the Rheumatoid Arthritis Synovial Membrane. J 2020. [DOI: 10.3390/j3020015] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Rheumatoid arthritis (RA) is a chronic inflammatory and destructive joint disease characterized by overexpression of pro-inflammatory/pro-destructive mediators, whose regulation has been the focus of our previous studies. Since the expression of these proteins commonly depends on AP-1, the expression of the AP-1-forming subunits cJun, JunB, JunD, and cFos was assessed in synovial membrane (SM) samples of RA, osteoarthritis (OA), joint trauma (JT), and normal controls (NC) using ELISA and qRT-PCR. With respect to an observed discrepancy between mRNA and protein levels, the expression of the mRNA stability-modifying factors AU-rich element RNA-binding protein (AUF)-1, tristetraprolin (TTP), and human antigen R (HuR) was measured. JunB and JunD protein expression was significantly higher in RA-SM compared to OA and/or NC. By contrast, jun/fos mRNA expression was significantly (cjun) or numerically decreased (junB, junD, cfos) in RA and OA compared to JT and/or NC. Remarkably, TTP and HuR were also affected by discrepancies between their mRNA and protein levels, since they were significantly decreased at the mRNA level in RA versus NC, but significantly or numerically increased at the protein level when compared to JT and NC. Discrepancies between the mRNA and protein expression for Jun/Fos and TTP/HuR suggest broad alterations of post-transcriptional processes in the RA-SM. In this context, increased levels of mRNA-destabilizing TTP may contribute to the low levels of jun/fos and ttp/hur mRNA, whereas abundant mRNA-stabilizing HuR may augment translation of the remaining mRNA into protein with potential consequences for the composition of the resulting AP-1 complexes and the expression of AP-1-dependent genes in RA.
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41
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Mu N, Gu JT, Huang TL, Liu NN, Chen H, Bu X, Zheng ZH, Jia B, Liu J, Wang BL, Wang YM, Zhu ZF, Zhang Y, Zhang YQ, Xue XC, Li M, Zhang W. Blockade of Discoidin Domain Receptor 2 as a Strategy for Reducing Inflammation and Joint Destruction in Rheumatoid Arthritis Via Altered Interleukin-15 and Dkk-1 Signaling in Fibroblast-Like Synoviocytes. Arthritis Rheumatol 2020; 72:943-956. [PMID: 32362074 DOI: 10.1002/art.41205] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Accepted: 01/09/2020] [Indexed: 12/12/2022]
Abstract
OBJECTIVE This study was undertaken to uncover the pathophysiologic role of discoidin domain receptor 2 (DDR-2), a putative fibrillar collagen receptor, in inflammation promotion and joint destruction in rheumatoid arthritis (RA). METHODS In synovial tissue from patients with RA and from mice with collagen antibody-induced arthritis (CAIA) (using Ddr2-/- and DBA/1 mice), gene and protein expression levels of DDR-2, interleukin-15 (IL-15), and Dkk-1 were measured by quantitative reverse transcription-polymerase chain reaction, Western blotting, and immunohistochemistry. Gene knockdown of DDR2 in human RA fibroblast-like synoviocytes (FLS) was conducted via small interfering RNA. Interaction between the long noncoding RNA H19 and microRNA 103a (miR-103a) was assessed in RA FLS using RNA pulldown assays. Cellular localization of H19 was examined using fluorescence in situ hybridization assays. Chromatin immunoprecipitation and dual luciferase reporter assays were applied to verify H19 transcriptional and posttranscriptional regulation by miR-103a. RESULTS DDR2 messenger RNA (mRNA) expression was significantly associated with the levels of IL-15 and Dkk-1 mRNA in the synovial tissue of RA patients (r2 = 0.2022-0.3293, all P < 0.05; n = 33) and with the serum levels of IL-15 and Dkk-1 in mice with CAIA (P < 0.05). In human RA FLS, activated DDR-2 induced the expression of H19 through c-Myc. Moreover, H19 directly interacted with and promoted the degradation of miR-103a. CONCLUSION These results indicate a novel role for activated DDR-2 in RA FLS, showing that DDR-2 is responsible for regulating the expression of IL-15 and Dkk-1 in RA FLS and is involved in the promotion of inflammation and joint destruction during pathophysiologic development of RA. Moreover, DDR-2 inhibition, acting through the H19-miR-103a axis, leads to reductions in the inflammatory reaction and severity of joint destruction in mice with CAIA, suggesting that inhibition of DDR-2 may be a potential therapeutic strategy for RA.
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Affiliation(s)
- Nan Mu
- Fourth Military Medical University, Xi'an, China
| | - Jin-Tao Gu
- Fourth Military Medical University, Xi'an, China
| | | | - Nan-Nan Liu
- Fourth Military Medical University, Xi'an, China
| | - Hui Chen
- Fourth Military Medical University, Xi'an, China
| | - Xin Bu
- Fourth Military Medical University, Xi'an, China
| | - Zhao-Hui Zheng
- Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Bo Jia
- Fourth Military Medical University, Xi'an, China
| | - Jun Liu
- Fourth Military Medical University, Xi'an, China
| | | | - Ying-Mei Wang
- Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Zhen-Feng Zhu
- Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Yong Zhang
- Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | | | | | - Meng Li
- Fourth Military Medical University, Xi'an, China
| | - Wei Zhang
- Fourth Military Medical University, Xi'an, China
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Fang Y, Tu J, Han D, Guo Y, Hong W, Wei W. The effects of long non-coding ribonucleic acids on various cellular components in rheumatoid arthritis. Rheumatology (Oxford) 2020; 59:46-56. [PMID: 31605483 PMCID: PMC6909907 DOI: 10.1093/rheumatology/kez472] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Revised: 09/07/2019] [Indexed: 01/13/2023] Open
Abstract
RA is a chronic, autoimmune-mediated inflammatory pathology. Long non-coding RNAs (lncRNAs) are a novel group of non-coding RNAs with a length of >200 nucleotides. There are reports emerging that suggest that lncRNAs participate in establishing and sustaining autoimmune diseases, including RA. In this review article, we highlight the functions of lncRNAs in different cell types in RA. Our review indicates that lncRNAs affect various cellular components and are novel candidates that could constitute promising targets for the diagnosis and treatment of RA.
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Affiliation(s)
- Yilong Fang
- Institute of Clinical Pharmacology, Hefei, China.,Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Anhui Medical University, Hefei, China
| | - Jiajie Tu
- Institute of Clinical Pharmacology, Hefei, China.,Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Anhui Medical University, Hefei, China
| | - Dafei Han
- Institute of Clinical Pharmacology, Hefei, China.,Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Anhui Medical University, Hefei, China
| | - Yawei Guo
- Institute of Clinical Pharmacology, Hefei, China.,Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Anhui Medical University, Hefei, China
| | - Wenming Hong
- Institute of Clinical Pharmacology, Hefei, China.,Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Anhui Medical University, Hefei, China
| | - Wei Wei
- Institute of Clinical Pharmacology, Hefei, China.,Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Anhui Medical University, Hefei, China
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43
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Zou Y, Xu H. Involvement of long noncoding RNAs in the pathogenesis of autoimmune diseases. J Transl Autoimmun 2020; 3:100044. [PMID: 32743525 PMCID: PMC7388364 DOI: 10.1016/j.jtauto.2020.100044] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2020] [Accepted: 03/08/2020] [Indexed: 02/07/2023] Open
Abstract
Autoimmune diseases are a group of heterogeneous disorders characterized by damage to various organs caused by abnormal innate and adaptive immune responses. The pathogenesis of autoimmune diseases is extremely complicated and has not yet been fully elucidated. Long noncoding RNAs (lncRNAs), which are defined as transcripts containing more than 200 nucleotides with no protein-coding capacity, are emerging as important regulators of gene expression via epigenetic modification, transcriptional regulation and posttranscriptional regulation. Accumulating evidence has demonstrated that lncRNAs play a key role in the regulation of immunological functions and autoimmunity. In this review, we discuss various molecular mechanisms by which lncRNAs regulate gene expression and recent findings regarding the involvement of lncRNAs in many human autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), idiopathic inflammatory myopathy (IIM), systemic sclerosis (SSc) and Sjögren’s syndrome (pSS).
lncRNAs are observed to be differentially expressed in various autoimmune diseases. lncRNAs are involved in abnormal immune regulation and inflammatory responses in autoimmune diseases, which provides new insight into disease pathogenesis. LncRNAs may have the potential of biomarkers for diagnosis and prognosis of autoimmune diseases.
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Affiliation(s)
- Yaoyao Zou
- Department of Rheumatology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Hanshi Xu
- Department of Rheumatology and Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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Abbasifard M, Kamiab Z, Bagheri-Hosseinabadi Z, Sadeghi I. The role and function of long non-coding RNAs in osteoarthritis. Exp Mol Pathol 2020; 114:104407. [PMID: 32088191 DOI: 10.1016/j.yexmp.2020.104407] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Revised: 01/03/2020] [Accepted: 02/19/2020] [Indexed: 12/20/2022]
Abstract
Osteoarthiritis (OA) is the most prevalent disease of articulating joints in human that frequently results in joint pain, movement limitations, inflammation, and progressive degradation of articular cartilage. The etiology of OA is not completely clear and there is no full treatment for this disease. Molecular investigations have revealed the involvement of non-coding RNAs such as Long non-coding RNAs (lncRNAs) in OA pathogenesis. LncRNAs play roles in multiple cellular and biological processes. Moreover, numerous lncRNAs are differentially expressed in human OA cartilage. In this review, we underlie the increasing evidence for the critical role of lncRNAs in OA pathogenesis reviewing the latest researches.
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Affiliation(s)
- Mitra Abbasifard
- Department of Internal Medicine, Ali-Ibn Abi-Talib Hospital, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Zahra Kamiab
- Department of Family Medicine, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; Clinical Research Development Unit, Ali Ibn Abi Talib Hospital, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Zahra Bagheri-Hosseinabadi
- Department of Clinical Biochemistry, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.
| | - Iman Sadeghi
- Centre for Genomic Regulation (CRG), The Barcelona Institute for Science and Technology, Dr. Aiguader 88, Barcelona, E-08003 Catalonia, Spain; CEINGE-biotecnologie avanzate, Naples, Italy.
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Long non-coding RNAs in immune regulation and their potential as therapeutic targets. Int Immunopharmacol 2020; 81:106279. [PMID: 32058929 DOI: 10.1016/j.intimp.2020.106279] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Revised: 01/30/2020] [Accepted: 02/01/2020] [Indexed: 12/18/2022]
Abstract
Long non-coding RNAs (lncRNAs) are potent regulators of immune cell development and function. Their implication in multiple immune-mediated disorders highlights lncRNAs as exciting biomarkers and potential drug targets. Recent technological innovations in oligo-based therapeutics, development of RNA-targeting small molecules, and CRISPR-based approaches, position RNA as the next therapeutic frontier. Here, we review the latest advances made toward understanding the role of lncRNAs in human immunological disorders and further discuss RNA-targeting approaches that could be potentially exploited to manipulate lncRNA function as a clinical intervention.
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Wang J, Yan S, Yang J, Lu H, Xu D, Wang Z. Non-coding RNAs in Rheumatoid Arthritis: From Bench to Bedside. Front Immunol 2020; 10:3129. [PMID: 32047497 PMCID: PMC6997467 DOI: 10.3389/fimmu.2019.03129] [Citation(s) in RCA: 110] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Accepted: 12/23/2019] [Indexed: 12/14/2022] Open
Abstract
Rheumatoid arthritis is a common systemic and autoimmune disease characterized by symmetrical and inflammatory destruction of distal joints. Its primary pathological characters are synovitis and vasculitis. Accumulating studies have implicated the critical role of non-coding RNAs (ncRNAs) in inflammation and autoimmune regulation, primarily including microRNA (miRNA), long non-coding RNA (lncRNA), and circular RNA (circRNA). NcRNAs are significant regulators in distinct physiological and pathophysiological processes. Many validated non-coding RNAs have been identified as promising biomarkers for the diagnosis and treatment of RA. This review will shed some light on RA pathogenesis and be helpful for identifying potential ncRNA biomarkers for RA.
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Affiliation(s)
- Jinghua Wang
- Clinical Medicine College, Weifang Medical University, Weifang, China.,Department of Rheumatology, The Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Shushan Yan
- Department of Gastrointestinal and Anal Diseases Surgery, The Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Jinghan Yang
- Clinical Medicine College, Weifang Medical University, Weifang, China.,Department of Rheumatology, The Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Hongying Lu
- Functional Laboratory, Clinical Medicine College of Weifang Medical University, Weifang, China
| | - Donghua Xu
- Clinical Medicine College, Weifang Medical University, Weifang, China.,Department of Rheumatology, The Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Zengyan Wang
- Department of Operating Room, Zhucheng People's Hospital, Zhucheng, China
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Ahmad I, Valverde A, Ahmad F, Naqvi AR. Long Noncoding RNA in Myeloid and Lymphoid Cell Differentiation, Polarization and Function. Cells 2020; 9:cells9020269. [PMID: 31979061 PMCID: PMC7072530 DOI: 10.3390/cells9020269] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Revised: 01/15/2020] [Accepted: 01/20/2020] [Indexed: 12/13/2022] Open
Abstract
Long noncoding RNA (lncRNA) are a class of endogenous, non-protein coding RNAs that are increasingly being associated with various cellular functions and diseases. Yet, despite their ubiquity and abundance, only a minute fraction of these molecules has an assigned function. LncRNAs show tissue-, cell-, and developmental stage-specific expression, and are differentially expressed under physiological or pathological conditions. The role of lncRNAs in the lineage commitment of immune cells and shaping immune responses is becoming evident. Myeloid cells and lymphoid cells are two major classes of immune systems that work in concert to initiate and amplify innate and adaptive immunity in vertebrates. In this review, we provide mechanistic roles of lncRNA through which these noncoding RNAs can directly participate in the differentiation, polarization, and activation of myeloid (monocyte, macrophage, and dendritic cells) and lymphoid cells (T cells, B cells, and NK cells). While our knowledge on the role of lncRNA in immune cell differentiation and function has improved in the past decade, further studies are required to unravel the biological role of lncRNAs and identify novel mechanisms of lncRNA functions in immune cells. Harnessing the regulatory potential of lncRNAs can provide novel diagnostic and therapeutic targets in treating immune cell related diseases.
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48
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Decreased H19, GAS5, and linc0597 Expression and Association Analysis of Related Gene Polymorphisms in Rheumatoid Arthritis. Biomolecules 2019; 10:biom10010055. [PMID: 31905737 PMCID: PMC7022387 DOI: 10.3390/biom10010055] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 12/18/2019] [Accepted: 12/26/2019] [Indexed: 01/06/2023] Open
Abstract
Long noncoding RNAs (lncRNAs) widely participate in human diseases by regulating gene transcription, modulating protein function, or acting as ceRNAs. Yet, their roles in rheumatoid arthritis (RA) remain obscure. In this study, the expression of three lncRNAs (H19, GAS5, and linc0597) in peripheral blood mononuclear cells (PBMCs) were detected in 77 RA patients and 78 controls using quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). The association of lncRNAs related gene polymorphisms with RA were evaluated in 828 RA patients and 780 controls using TaqMan single nucleotide polymorphism (SNP) genotyping assays. We observed that the expression levels of H19, GAS5 and linc0597 were down-regulated in PBMCs of RA patients, of which GAS5 level decreased in patients with hypocomplementemia, and negatively correlated with C-reactive protein (CRP) level in RA patients. Moreover, we highlighted two related potential functional SNPs, GAS5 rs6790 and linc0597 rs2680700 for associations with RA susceptibility. The precise roles of these lncRNAs in mechanism of RA remain to be further explored.
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lncRNA-Triggered Macrophage Inflammaging Deteriorates Age-Related Diseases. Mediators Inflamm 2019; 2019:4260309. [PMID: 31949425 PMCID: PMC6942909 DOI: 10.1155/2019/4260309] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Revised: 11/10/2019] [Accepted: 11/13/2019] [Indexed: 02/05/2023] Open
Abstract
Aging and age-related diseases (ARDs) share basic mechanisms largely involving inflammation. A chronic, low-grade, subclinical inflammation called inflammaging occurs during aging. Autophagy defects, oxidative stresses, senescence-associated secretory phenotypes (SASPs), and DNA damage generally contribute to inflammaging and are largely regulated by numerous lncRNA through two-level vicious cycles disrupting cellular homeostasis: (1) inflammaging and the cellular senescence cascade and (2) autophagy defects, oxidative stress, and the SASP cascade. SASPs and inflammasomes simultaneously cause inflammaging. This review discusses the involvement of macrophage inflammaging in various ARDs and its regulation via lncRNA. Among macrophages, this phenomenon potentially impairs its immunosurveillance and phagocytosis mechanisms, leading to decreased recognition and clearance of malignant and senescent cells. Moreover, SASPs extracellularly manifest to induce paracrine senescence. Macrophage senescence escalates to organ level malfunction, and the organism is more prone to ARDs. By targeting genes and proteins or functioning as competing endogenous RNA (ceRNA), lncRNA regulates different phenomena including inflammaging and ARDs. The detailed mechanism warrants further elucidation to obtain pathological evidence of ARDs and potential treatment approaches.
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H19 Increases IL-17A/IL-23 Releases via Regulating VDR by Interacting with miR675-5p/miR22-5p in Ankylosing Spondylitis. MOLECULAR THERAPY-NUCLEIC ACIDS 2019; 19:393-404. [PMID: 31887550 PMCID: PMC6938967 DOI: 10.1016/j.omtn.2019.11.025] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/11/2019] [Revised: 11/03/2019] [Accepted: 11/22/2019] [Indexed: 01/01/2023]
Abstract
Long non-coding RNA (lncRNA) H19 is associated with inflammatory diseases, but the molecular mechanism of H19 in the inflammatory process of ankylosing spondylitis (AS) is unclear. Here, we investigated the role of H19 and its downstream molecules in the inflammation of AS by microarray analysis, qRT-PCR, western blot, and dual-luciferase reporter assay. H19 small interfering RNA (siRNA) (Si-H19) and adenovirus (AD-H19) were used to decrease and increase H19 expression, respectively. 42 annotated lncRNAs were identified, and H19 was overexpressed. H19, vitamin D receptor (VDR), and transforming growth factor β (TGF-β) can bind to microRNA22-5p (miR22-5p) and miR675-5p. Si-H19 significantly downregulated miR22-5p and upregulated miR675-5p expression; Si-H19 decreased the protein and mRNA expression of VDR and decreased the cytokine and mRNA levels of interleukin-17A (IL-17A) and IL-23. These results were verified by AD-H19. In addition, miR22-5p and miR675-5p inhibitors increased the protein and mRNA expression of VDR and increased the cytokine and mRNA levels of IL-17A and IL-23. These results were also confirmed by miRNA mimics. Furthermore, H19 directly interfered with miR22-5p and miR675-5p expression, whereas the two miRNAs directly inhibited VDR expression. Overall, the H19-miR22-5p/miR675-5p-VDR-IL-17A/IL-23 signaling pathways have important roles in the pathogenesis of AS.
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