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Huang Y, Wang Z. Therapeutic potential of SOX family transcription factors in osteoarthritis. Ann Med 2025; 57:2457520. [PMID: 39887675 PMCID: PMC11789227 DOI: 10.1080/07853890.2025.2457520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2024] [Revised: 12/27/2024] [Accepted: 01/02/2025] [Indexed: 02/01/2025] Open
Abstract
BACKGROUND As the worldwide population ages, osteoarthritis has significantly increased. This musculoskeletal condition has become a pressing global health issue and thus, prevention and treatment of osteoarthritis have become the primary focus of domestic and international research. Scholarly investigations of the molecular mechanisms that are related to the occurrence and development of osteoarthritis have shed light on the pathological causes of this condition to a certain extent, providing a foundation for its prevention and treatment. However, further research is necessary to fully understand the critical role of the transcription factor SOX9 in chondrocyte differentiation and the development of osteoarthritis. As a result, there has been widespread interest in SOX transcription factors. While SOX9 has been utilized as a biomarker to indicate the occurrence and prognosis of osteoarthritis, investigations into other members of the SOX family and the development of targeted treatments around SOX9 are still required. PURPOSE This article considers the impact of the SOX protein on the development and inhibition of osteoarthritis and highlights the need for therapeutic approaches targeting SOX9, as supported by existing research. RESULTS SOX9 can contribute to the process of osteoarthritis through acetylation and ubiquitination modifications. The regulation of the WNT signalling pathway, Nrf2/ARE signalling pathway, NF-κB signalling pathway and SOX9 is implicated in the emergence of osteoarthritis. Non-coding RNA may play a role in the onset and progression of osteoarthritis by modulating various SOX family members, including SOX2, SOX4, SOX5, SOX6, SOX8, SOX9 and SOX11. CONCLUSION SOX9 has the capability of mitigating the onset and progression of osteoarthritis through means such as medication therapy, stem cell therapy, recombinant adeno-associated virus (rAAV) vector therapy, physical therapy and other approaches.
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Affiliation(s)
- Yue Huang
- College of Exercise and Health, Shenyang Sport University, Shenyang, China
| | - Zhuo Wang
- College of Exercise and Health, Shenyang Sport University, Shenyang, China
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2
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Jia B, Han X, Li X, Zhang L, Ma F, Wang Y, Wang X, Yan Y, Li Y, Shen J, Chen X, Li X, Zhang Q, Hu P, Du R. Deer antler reserve mesenchyme cells modified with miR-145 promote chondrogenesis in cartilage regeneration. Front Vet Sci 2024; 11:1500969. [PMID: 39776601 PMCID: PMC11705092 DOI: 10.3389/fvets.2024.1500969] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Accepted: 12/09/2024] [Indexed: 01/11/2025] Open
Abstract
Deer antler-derived reserve mesenchyme cells (RMCs) are a promising source of cells for cartilage regeneration therapy due to their chondrogenic differentiation potential. However, the regulatory mechanism has not yet been elucidated. In this study, we analyzed the role of microRNAs (miRNAs) in regulating the differentiation of RMCs and in the post-transcriptional regulation of chondrogenesis and hypertrophic differentiation at the molecular and histological levels. The results showed that RMCs showed typical MSC differentiation potentials. During chondrogenic differentiation, we obtained the expression profile of miRNAs, among which miR- 145 was the most prominent candidate as a key microRNA involved in the balance of chondral and endochondral differentiation. Knockdown of miR-145 promoted chondrogenesis and inhibited hypertrophy differentiation in RMCs. Mechanically, by prediction through online databases combined with dual-luciferase reporter assay, SOX9 was suggested as a target of miR-145. Further validation experiments confirmed that knockdown of miR-145 contributed to the balance between endochondral versus chondral differentiation of RMCs by targeting SOX9. Additionally, RMCs transfected with the miR-145-knockdown-mediated lentiviral vector successfully promoted cartilage regeneration in vivo. In summary, our study suggested that the reciprocal negative feedback between SOX9 and miR-145 was essential for balancing between endochondral versus chondral differentiation of RMCs. Our study suggested that modification of RMCs using miRNAs transduction might be an effective treatment for cartilage defects.
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Affiliation(s)
- Boyin Jia
- College of Animal Medicine/College of Animal Science and Technology, Jilin Agricultural University, Changchun, China
- Laboratory of Production and Product Application of Sika Deer of Jilin Province, Jilin Agricultural University, Changchun, China
| | - Xintong Han
- College of Animal Medicine/College of Animal Science and Technology, Jilin Agricultural University, Changchun, China
| | - Xin Li
- College of Animal Medicine/College of Animal Science and Technology, Jilin Agricultural University, Changchun, China
| | - Linlin Zhang
- College of Animal Medicine/College of Animal Science and Technology, Jilin Agricultural University, Changchun, China
| | - Fuquan Ma
- College of Animal Medicine/College of Animal Science and Technology, Jilin Agricultural University, Changchun, China
| | - Yusu Wang
- Laboratory of Production and Product Application of Sika Deer of Jilin Province, Jilin Agricultural University, Changchun, China
| | - Xue Wang
- College of Animal Medicine/College of Animal Science and Technology, Jilin Agricultural University, Changchun, China
| | - Yaru Yan
- College of Animal Medicine/College of Animal Science and Technology, Jilin Agricultural University, Changchun, China
| | - Yaxin Li
- College of Animal Medicine/College of Animal Science and Technology, Jilin Agricultural University, Changchun, China
| | - Junnan Shen
- College of Animal Medicine/College of Animal Science and Technology, Jilin Agricultural University, Changchun, China
| | - Xinran Chen
- College of Animal Medicine/College of Animal Science and Technology, Jilin Agricultural University, Changchun, China
| | - Xinyi Li
- College of Animal Medicine/College of Animal Science and Technology, Jilin Agricultural University, Changchun, China
| | - Qianzhen Zhang
- College of Animal Medicine/College of Animal Science and Technology, Jilin Agricultural University, Changchun, China
| | - Pengfei Hu
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun, China
| | - Rui Du
- Laboratory of Production and Product Application of Sika Deer of Jilin Province, Jilin Agricultural University, Changchun, China
- Yanbian University, Yanbian, China
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Villagrán-Andrade KM, Núñez-Carro C, Blanco FJ, de Andrés MC. Nutritional Epigenomics: Bioactive Dietary Compounds in the Epigenetic Regulation of Osteoarthritis. Pharmaceuticals (Basel) 2024; 17:1148. [PMID: 39338311 PMCID: PMC11434976 DOI: 10.3390/ph17091148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 08/24/2024] [Accepted: 08/27/2024] [Indexed: 09/30/2024] Open
Abstract
Nutritional epigenomics is exceptionally important because it describes the complex interactions among food compounds and epigenome modifications. Phytonutrients or bioactive compounds, which are secondary metabolites of plants, can protect against osteoarthritis by suppressing the expression of inflammatory and catabolic mediators, modulating epigenetic changes in DNA methylation, and the histone or chromatin remodelling of key inflammatory genes and noncoding RNAs. The combination of natural epigenetic modulators is crucial because of their additive and synergistic effects, safety and therapeutic efficacy, and lower adverse effects than conventional pharmacology in the treatment of osteoarthritis. In this review, we have summarized the chondroprotective properties of bioactive compounds used for the management, treatment, or prevention of osteoarthritis in both human and animal studies. However, further research is needed into bioactive compounds used as epigenetic modulators in osteoarthritis, in order to determine their potential value for future clinical applications in osteoarthritic patients as well as their relation with the genomic and nutritional environment, in order to personalize food and nutrition together with disease prevention.
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Affiliation(s)
- Karla Mariuxi Villagrán-Andrade
- Unidad de Epigenética, Grupo de Investigación en Reumatología (GIR), Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario, de A Coruña (CHUAC), Sergas, 15006 A Coruña, Spain
| | - Carmen Núñez-Carro
- Unidad de Epigenética, Grupo de Investigación en Reumatología (GIR), Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario, de A Coruña (CHUAC), Sergas, 15006 A Coruña, Spain
| | - Francisco J Blanco
- Unidad de Epigenética, Grupo de Investigación en Reumatología (GIR), Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario, de A Coruña (CHUAC), Sergas, 15006 A Coruña, Spain
- Grupo de Investigación en Reumatología y Salud, Departamento de Fisioterapia, Medicina y Ciencias Biomédicas, Facultad de Fisioterapia, Campus de Oza, Universidade da Coruña (UDC), 15008 A Coruña, Spain
| | - María C de Andrés
- Unidad de Epigenética, Grupo de Investigación en Reumatología (GIR), Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario, de A Coruña (CHUAC), Sergas, 15006 A Coruña, Spain
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Sulcanese L, Prencipe G, Canciello A, Cerveró-Varona A, Perugini M, Mauro A, Russo V, Barboni B. Stem-Cell-Driven Chondrogenesis: Perspectives on Amnion-Derived Cells. Cells 2024; 13:744. [PMID: 38727280 PMCID: PMC11083072 DOI: 10.3390/cells13090744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Revised: 04/17/2024] [Accepted: 04/23/2024] [Indexed: 05/13/2024] Open
Abstract
Regenerative medicine harnesses stem cells' capacity to restore damaged tissues and organs. In vitro methods employing specific bioactive molecules, such as growth factors, bio-inductive scaffolds, 3D cultures, co-cultures, and mechanical stimuli, steer stem cells toward the desired differentiation pathways, mimicking their natural development. Chondrogenesis presents a challenge for regenerative medicine. This intricate process involves precise modulation of chondro-related transcription factors and pathways, critical for generating cartilage. Cartilage damage disrupts this process, impeding proper tissue healing due to its unique mechanical and anatomical characteristics. Consequently, the resultant tissue often forms fibrocartilage, which lacks adequate mechanical properties, posing a significant hurdle for effective regeneration. This review comprehensively explores studies showcasing the potential of amniotic mesenchymal stem cells (AMSCs) and amniotic epithelial cells (AECs) in chondrogenic differentiation. These cells exhibit innate characteristics that position them as promising candidates for regenerative medicine. Their capacity to differentiate toward chondrocytes offers a pathway for developing effective regenerative protocols. Understanding and leveraging the innate properties of AMSCs and AECs hold promise in addressing the challenges associated with cartilage repair, potentially offering superior outcomes in tissue regeneration.
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Affiliation(s)
- Ludovica Sulcanese
- Unit of Basic and Applied Sciences, Department of Biosciences and Agri-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy; (G.P.); (A.C.); (A.C.-V.); (A.M.); (V.R.); (B.B.)
| | - Giuseppe Prencipe
- Unit of Basic and Applied Sciences, Department of Biosciences and Agri-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy; (G.P.); (A.C.); (A.C.-V.); (A.M.); (V.R.); (B.B.)
| | - Angelo Canciello
- Unit of Basic and Applied Sciences, Department of Biosciences and Agri-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy; (G.P.); (A.C.); (A.C.-V.); (A.M.); (V.R.); (B.B.)
| | - Adrián Cerveró-Varona
- Unit of Basic and Applied Sciences, Department of Biosciences and Agri-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy; (G.P.); (A.C.); (A.C.-V.); (A.M.); (V.R.); (B.B.)
| | - Monia Perugini
- Department of Bioscience and Technology for Food, Agriculture, and Environment, University of Teramo, 64100 Teramo, Italy;
| | - Annunziata Mauro
- Unit of Basic and Applied Sciences, Department of Biosciences and Agri-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy; (G.P.); (A.C.); (A.C.-V.); (A.M.); (V.R.); (B.B.)
| | - Valentina Russo
- Unit of Basic and Applied Sciences, Department of Biosciences and Agri-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy; (G.P.); (A.C.); (A.C.-V.); (A.M.); (V.R.); (B.B.)
| | - Barbara Barboni
- Unit of Basic and Applied Sciences, Department of Biosciences and Agri-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy; (G.P.); (A.C.); (A.C.-V.); (A.M.); (V.R.); (B.B.)
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Zhang Y, Wang Q, Xue H, Guo Y, Wei S, Li F, Gong L, Pan W, Jiang P. Epigenetic Regulation of Autophagy in Bone Metabolism. FUNCTION 2024; 5:zqae004. [PMID: 38486976 PMCID: PMC10935486 DOI: 10.1093/function/zqae004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Revised: 01/18/2024] [Accepted: 01/24/2024] [Indexed: 03/17/2024] Open
Abstract
The skeletal system is crucial for supporting bodily functions, protecting vital organs, facilitating hematopoiesis, and storing essential minerals. Skeletal homeostasis, which includes aspects such as bone density, structural integrity, and regenerative processes, is essential for normal skeletal function. Autophagy, an intricate intracellular mechanism for degrading and recycling cellular components, plays a multifaceted role in bone metabolism. It involves sequestering cellular waste, damaged proteins, and organelles within autophagosomes, which are then degraded and recycled. Autophagy's impact on bone health varies depending on factors such as regulation, cell type, environmental cues, and physiological context. Despite being traditionally considered a cytoplasmic process, autophagy is subject to transcriptional and epigenetic regulation within the nucleus. However, the precise influence of epigenetic regulation, including DNA methylation, histone modifications, and non-coding RNA expression, on cellular fate remains incompletely understood. The interplay between autophagy and epigenetic modifications adds complexity to bone cell regulation. This article provides an in-depth exploration of the intricate interplay between these two regulatory paradigms, with a focus on the epigenetic control of autophagy in bone metabolism. Such an understanding enhances our knowledge of bone metabolism-related disorders and offers insights for the development of targeted therapeutic strategies.
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Affiliation(s)
- Yazhou Zhang
- Department of Foot and Ankle Surgery, Tengzhou Central People’s Hospital, Tengzhou 277500, China
| | - Qianqian Wang
- Department of Pediatric Intensive Care Unit, Tengzhou Central People’s Hospital, Tengzhou 277500, China
| | - Hongjia Xue
- Department of Computer Science, University College London, London, WC1E 6BT, UK
| | - Yujin Guo
- Institute of Clinical Pharmacy & Pharmacology, Jining First People’s Hospital, Jining 272000, China
| | - Shanshan Wei
- Department of Pharmacy, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250000, China
- Department of Graduate, Shandong Academy of Medical Sciences, Shandong First Medical University, Jinan 250000, China
| | - Fengfeng Li
- Department of Neurosurgery, Tengzhou Central People’s Hospital, Tengzhou 277500, China
| | - Linqiang Gong
- Department of Gastroenterology, Tengzhou Central People's Hospital, Tengzhou 277500, China
| | - Weiliang Pan
- Department of Foot and Ankle Surgery, Tengzhou Central People’s Hospital, Tengzhou 277500, China
| | - Pei Jiang
- Translational Pharmaceutical Laboratory, Jining First People’s Hospital, Shandong First Medical University, Jining 272000, China
- Institute of Translational Pharmacy, Jining Medical Research Academy, Jining 272000, China
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Raoufinia R, Afrasiabi P, Dehghanpour A, Memarpour S, Hosseinian SHS, Saburi E, Naghipoor K, Rezaei S, Haghmoradi M, Keyhanvar N, Rostami M, Fakoor F, Kazemi MI, Moghbeli M, Rahimi HR. The Landscape of microRNAs in Bone Tumor: A Comprehensive Review in Recent Studies. Microrna 2024; 13:175-201. [PMID: 39005129 DOI: 10.2174/0122115366298799240625115843] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Revised: 04/11/2024] [Accepted: 05/23/2024] [Indexed: 07/16/2024]
Abstract
Cancer, the second greatest cause of mortality worldwide, frequently causes bone metastases in patients with advanced-stage carcinomas such as prostate, breast, and lung cancer. The existence of these metastases contributes to the occurrence of skeletal-related events (SREs), which are defined by excessive pain, pathological fractures, hypercalcemia, and spinal cord compression. These injurious incidents leave uncomfortably in each of the cancer patient's life quality. Primary bone cancers, including osteosarcoma (OS), chondrosarcoma (CS), and Ewing's sarcoma (ES), have unclear origins. MicroRNA (miRNA) expression patterns have been changed in primary bone cancers such as OS, CS, and ES, indicating a role in tumor development, invasion, metastasis, and treatment response. These miRNAs are persistent in circulation and exhibit distinct patterns in many forms of bone tumors, making them potential biomarkers for early detection and treatment of such diseases. Given their crucial regulatory functions in various biological processes and conditions, including cancer, this study aims to look at miRNAs' activities and possible contributions to bone malignancies, focusing on OS, CS, and ES. In conclusion, miRNAs are valuable tools for diagnosing, monitoring, and predicting OS, CS, and ES outcomes. Further research is required to fully comprehend the intricate involvement of miRNAs in these bone cancers and to develop effective miRNA-based treatments.
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Affiliation(s)
- Ramin Raoufinia
- Noncommunicable Diseases Research Center, Neyshabur University of Medical Sciences, Neyshabur, Iran
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Parisa Afrasiabi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Amir Dehghanpour
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Sara Memarpour
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Ehsan Saburi
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Karim Naghipoor
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Samaneh Rezaei
- Vascular and Endovascular Surgery Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Meisam Haghmoradi
- Orthopedic Research Center, Shahid Kamyab Hospital, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Neda Keyhanvar
- Department of Biochemistry & Biophysics, University of California San Francisco, San Francisco, CA, 94107, USA
| | - Mehdi Rostami
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Farhad Fakoor
- Department of Paramedical Sciences, Iran University of Medical Sciences, Tehran, Iran
| | - Mohammadali Izadpanah Kazemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Meysam Moghbeli
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hamid Reza Rahimi
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Vascular and Endovascular Surgery Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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Ji Y, Xiong L, Zhang G, Xu M, Qiu W, Xiu C, Kuang G, Rui Y. Synovial fluid exosome-derived miR-182-5p alleviates osteoarthritis by downregulating TNFAIP8 and promoting autophagy through LC3 signaling. Int Immunopharmacol 2023; 125:111177. [PMID: 37948986 DOI: 10.1016/j.intimp.2023.111177] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 10/30/2023] [Accepted: 11/01/2023] [Indexed: 11/12/2023]
Abstract
OBJECTIVE To investigate the role of exosomal miRNAs from synovial fluid (SF) in osteoarthritis (OA) patients and investigate the underlying molecular mechanism. METHODS Degenerated knee tissues were collected from male and female OA patients. Enzyme-linked immunosorbent assay (ELISA) was used to detect the differences in the expression of inflammatory indicators, including TNF-α, IL-6, and IL-10, between the degenerative and injury groups. Exosomes were isolated from SF using the Exoquick kit, and a microarray was used to identify differentially expressed miRNAs (DEmiRNAs), which were analyzed using bioinformatics. The predicted relationship between DEmiRNAs and target genes was verified using a luciferase reporter gene assay. CCK-8 and transwell assays were used to assess cell viability and migration. Immunofluorescence and TUNEL assay were used to detect cell autophagy and apoptosis. The interaction between proteins was detected by immunoprecipitation and verified by Mab rescue assay. RESULTS The relative expression of TNF-α/IL6 was significantly higher in the degeneration group than in the injury group. The OA degeneration group released significantly more and smaller exosomes than the injury group. The expression of miR-182-5p was markedly reduced in OA patients and had a higher correlation with inflammatory indicators. Tumor necrosis factor α-induced protein 8 (TNFAIP8) was a target of miR-182-5p, and its overexpression promoted chondrocyte proliferation, migration, and invasion and enhanced the wound healing efficiency. We also found a direct interaction of TNFAIP8 with autophagy-related gene 3 (ATG3). TNFAIP8 triggered ATG3 LC3-mediated autophagy. CONCLUSION The downregulation of exosomal miR-182-5p inhibits OA degeneration by targeting TNFAIP8 via the ATG/LC3 pathway.
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Affiliation(s)
- Yunhan Ji
- Suzhou Medical College of Soochow University, Jiangsu, Suzhou 215000, China; Department of Orthopedic, Wuxi 9th Affiliated Hospital of Soochow University, Jiangsu, Wuxi 214062, China; Department of Orthopedic Surgery, Tongren Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200336, China
| | - Li Xiong
- Department of Orthopedic Surgery, Tongren Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200336, China
| | - Gonghao Zhang
- Department of Orthopedic Surgery, Tongren Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200336, China
| | - Mingze Xu
- Department of Orthopedic Surgery, Tongren Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200336, China
| | - Wenjun Qiu
- Department of Orthopedic Surgery, Tongren Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200336, China
| | - Chaoyang Xiu
- Department of Orthopedic Surgery, Tongren Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200336, China
| | - Gaixia Kuang
- Department of Orthopedic Surgery, Tongren Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200336, China
| | - Yongjun Rui
- Department of Orthopedic, Wuxi 9th Affiliated Hospital of Soochow University, Jiangsu, Wuxi 214062, China.
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Wells LM, Roberts HC, Luyten FP, Roberts SJ. Identifying Fibroblast Growth Factor Receptor 3 as a Mediator of Periosteal Osteochondral Differentiation through the Construction of microRNA-Based Interaction Networks. BIOLOGY 2023; 12:1381. [PMID: 37997980 PMCID: PMC10669632 DOI: 10.3390/biology12111381] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 10/13/2023] [Accepted: 10/24/2023] [Indexed: 11/25/2023]
Abstract
Human periosteum-derived progenitor cells (hPDCs) have the ability to differentiate towards both the chondrogenic and osteogenic lineages. This coordinated and complex osteochondrogenic differentiation process permits endochondral ossification and is essential in bone development and repair. We have previously shown that humanised cultures of hPDCs enhance their osteochondrogenic potentials in vitro and in vivo; however, the underlying mechanisms are largely unknown. This study aimed to identify novel regulators of hPDC osteochondrogenic differentiation through the construction of miRNA-mRNA regulatory networks derived from hPDCs cultured in human serum or foetal bovine serum as an alternative in silico strategy to serum characterisation. Sixteen differentially expressed miRNAs (DEMis) were identified in the humanised culture. In silico analysis of the DEMis with TargetScan allowed for the identification of 1503 potential miRNA target genes. Upon comparison with a paired RNAseq dataset, a 4.5% overlap was observed (122 genes). A protein-protein interaction network created with STRING interestingly identified FGFR3 as a key network node, which was further predicted using multiple pathway analyses. Functional analysis revealed that hPDCs with the activating mutation FGFR3N540K displayed increased expressions of chondrogenic gene markers when cultured under chondrogenic conditions in vitro and displayed enhanced endochondral bone formation in vivo. A further histological analysis uncovered known downstream mediators involved in FGFR3 signalling and endochondral ossification to be upregulated in hPDC FGFR3N540K-seeded implants. This combinational approach of miRNA-mRNA-protein network analysis with in vitro and in vivo characterisation has permitted the identification of FGFR3 as a novel mediator of hPDC biology. Furthermore, this miRNA-based workflow may also allow for the identification of drug targets, which may be of relevance in instances of delayed fracture repair.
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Affiliation(s)
- Leah M. Wells
- Department of Comparative Biomedical Sciences, The Royal Veterinary College, London NW1 0TU, UK;
| | - Helen C. Roberts
- Department of Natural Sciences, Middlesex University, London NW4 4BT, UK;
| | - Frank P. Luyten
- Skeletal Biology and Engineering Research Centre (SBE), KU Leuven, 3000 Leuven, Belgium;
| | - Scott J. Roberts
- Department of Comparative Biomedical Sciences, The Royal Veterinary College, London NW1 0TU, UK;
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Wakale S, Wu X, Sonar Y, Sun A, Fan X, Crawford R, Prasadam I. How are Aging and Osteoarthritis Related? Aging Dis 2023; 14:592-604. [PMID: 37191424 PMCID: PMC10187698 DOI: 10.14336/ad.2022.0831] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Accepted: 08/31/2022] [Indexed: 05/17/2023] Open
Abstract
Osteoarthritis is the most prevalent degenerative joint disease and one of the leading causes of physical impairment in the world's aging population. The human lifespan has significantly increased as a result of scientific and technological advancements. According to estimates, the world's elderly population will increase by 20% by 2050. Aging and age-related changes are discussed in this review in relation to the development of OA. We specifically discussed the cellular and molecular changes that occur in the chondrocytes during aging and how these changes may make synovial joints more susceptible to OA development. These changes include chondrocyte senescence, mitochondrial dysfunction, epigenetic modifications, and decreased growth factor response. The age-associated changes occur not only in the chondrocytes but also in the matrix, subchondral bone, and synovium. This review aims to provide an overview of the interplay between chondrocytes and matrix and how age-related changes affect the normal function of cartilage and contribute to OA development. Understanding the alterations that affect the function of chondrocytes will emerge new possibilities for prospective therapeutic options for the treatment of OA.
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Affiliation(s)
- Shital Wakale
- Centre for Biomedical Technologies, Faculty of Engineering, Queensland University of Technology, Brisbane, Queensland, Australia.
| | - Xiaoxin Wu
- Centre for Biomedical Technologies, Faculty of Engineering, Queensland University of Technology, Brisbane, Queensland, Australia.
| | - Yogita Sonar
- Centre for Biomedical Technologies, Faculty of Engineering, Queensland University of Technology, Brisbane, Queensland, Australia.
| | - Antonia Sun
- Centre for Biomedical Technologies, Faculty of Engineering, Queensland University of Technology, Brisbane, Queensland, Australia.
| | - Xiwei Fan
- Centre for Biomedical Technologies, Faculty of Engineering, Queensland University of Technology, Brisbane, Queensland, Australia.
| | - Ross Crawford
- Centre for Biomedical Technologies, Faculty of Engineering, Queensland University of Technology, Brisbane, Queensland, Australia.
- Orthopaedic Department, The Prince Charles Hospital, Brisbane, Queensland, Australia.
| | - Indira Prasadam
- Centre for Biomedical Technologies, Faculty of Engineering, Queensland University of Technology, Brisbane, Queensland, Australia.
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Yassin AM, AbuBakr HO, Abdelgalil AI, Farid OA, El-Behairy AM, Gouda EM. Circulating miR-146b and miR-27b are efficient biomarkers for early diagnosis of Equidae osteoarthritis. Sci Rep 2023; 13:7966. [PMID: 37198318 PMCID: PMC10192321 DOI: 10.1038/s41598-023-35207-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2022] [Accepted: 05/14/2023] [Indexed: 05/19/2023] Open
Abstract
One of the most orthopedic problems seen in the equine is osteoarthritis (OA). The present study tracks some biochemical, epigenetic, and transcriptomic factors along different stages of monoiodoacetate (MIA) induced OA in donkeys in serum and synovial fluid. The aim of the study was the detection of sensitive noninvasive early biomarkers. OA was induced by a single intra-articular injection of 25 mg of MIA into the left radiocarpal joint of nine donkeys. Serum and synovial samples were taken at zero-day and different intervals for assessment of total GAGs and CS levels as well as miR-146b, miR-27b, TRAF-6, and COL10A1 gene expression. The results showed that the total GAGs and CS levels increased in different stages of OA. The level of expression of both miR-146b and miR-27b were upregulated as OA progressed and then downregulated at late stages. TRAF-6 gene was upregulated at the late stage while synovial fluid COL10A1 was over-expressed at the early stage of OA and then decreased at the late stages (P < 0.05). In conclusion, both miR-146b and miR-27b together with COL10A1 could be used as promising noninvasive biomarkers for the very early diagnosis of OA.
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Affiliation(s)
- Aya M Yassin
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Cairo University, Giza, 12211, Egypt.
| | - Huda O AbuBakr
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Cairo University, Giza, 12211, Egypt
| | - Ahmed I Abdelgalil
- Department of Surgery, Anesthesiology, and Radiology, Faculty of Veterinary Medicine, Cairo University, Giza, 12211, Egypt
| | - Omar A Farid
- Department of Physiology, National Organization for Drug Control and Research, Giza, Egypt
| | - Adel M El-Behairy
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Cairo University, Giza, 12211, Egypt
| | - Eman M Gouda
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Cairo University, Giza, 12211, Egypt
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11
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Cong L, Jiang P, Wang H, Huang L, Wu G, Che X, Wang C, Li P, Duan Q, Guo X, Li P. MiR-1 is a critical regulator of chondrocyte proliferation and hypertrophy by inhibiting Indian hedgehog pathway during postnatal endochondral ossification in miR-1 overexpression transgenic mice. Bone 2022; 165:116566. [PMID: 36152943 DOI: 10.1016/j.bone.2022.116566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 09/18/2022] [Accepted: 09/19/2022] [Indexed: 11/02/2022]
Abstract
Endochondral bone formation from the growth plate plays a critical role in vertebrate limb development and skeletal homeostasis. Although miR-1 is mainly expressed in the hypertrophic region of the growth plate during this process, its role in the endochondral bone formation is unknown. To elucidate the role of miR-1 in cartilage development, chondrocyte-specific transgenic mice with high expression of miR-1 were generated (Col2a1-Cre-ERT2-GFPfl/fl-RFP-miR-1). Transgenic mice showed short limbs and delayed formation of secondary ossification centers. In the tibia growth plate of miR-1-overexpressing transgenic mice, the chondrocytes in the proliferative zone were disorganized and their proliferation decreased, and the ColX, MMP-13 and Indian Hedgehog (IHH) in chondrocytes showed a downward trend, resulting in decreased terminal differentiation in the hypertrophic zone. In addition, the apoptosis index caspase-3 also showed a downward trend in the tibia growth plate. It was concluded that miR-1 overexpression affects chondrocyte proliferation, hypertrophic differentiation, and apoptosis, thereby delaying the formation of secondary ossification centers and leading to short limbs. It was also verified that miR-1 affects endochondral ossification through the IHH pathway. The above results suggest that miR-1 overexpression can affect endochondral osteogenesis by inhibiting chondrocyte proliferation, hypertrophic differentiation, and apoptosis, thus causing limb hypoplasia in mice. This work gives potential for new therapeutic directions and insights for the treatment of dwarf-related diseases.
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Affiliation(s)
- Linlin Cong
- Key Laboratory of Bone and Soft Tissue Injury, Second Hospital of Shanxi Medical University, Taiyuan, China; Department of Biochemistry and Molecular Biology, College of Basic Medicine, Shanxi Medical University, Taiyuan, China
| | - Pinpin Jiang
- Key Laboratory of Bone and Soft Tissue Injury, Second Hospital of Shanxi Medical University, Taiyuan, China; The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Hang Wang
- Key Laboratory of Bone and Soft Tissue Injury, Second Hospital of Shanxi Medical University, Taiyuan, China; College of Basic Medical Sciences, Shanxi Medical University, Taiyuan, China
| | - Lingan Huang
- Key Laboratory of Bone and Soft Tissue Injury, Second Hospital of Shanxi Medical University, Taiyuan, China; The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Gaige Wu
- Key Laboratory of Bone and Soft Tissue Injury, Second Hospital of Shanxi Medical University, Taiyuan, China; The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Xianda Che
- Key Laboratory of Bone and Soft Tissue Injury, Second Hospital of Shanxi Medical University, Taiyuan, China; The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Chunfang Wang
- Laboratory Animal Center of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Penghua Li
- Department of Laboratory Medicine, Fenyang Hospital Affiliated to Shanxi Medical University, Fenyang, Shanxi, China
| | - Qianqian Duan
- Taiyuan University of Technology, Taiyuan, Shanxi, China
| | - Xing Guo
- Taiyuan University of Technology, Taiyuan, Shanxi, China
| | - Pengcui Li
- Key Laboratory of Bone and Soft Tissue Injury, Second Hospital of Shanxi Medical University, Taiyuan, China.
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12
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Lesage R, Ferrao Blanco MN, Narcisi R, Welting T, van Osch GJVM, Geris L. An integrated in silico-in vitro approach for identifying therapeutic targets against osteoarthritis. BMC Biol 2022; 20:253. [PMID: 36352408 PMCID: PMC9648005 DOI: 10.1186/s12915-022-01451-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Accepted: 10/27/2022] [Indexed: 11/11/2022] Open
Abstract
BACKGROUND Without the availability of disease-modifying drugs, there is an unmet therapeutic need for osteoarthritic patients. During osteoarthritis, the homeostasis of articular chondrocytes is dysregulated and a phenotypical transition called hypertrophy occurs, leading to cartilage degeneration. Targeting this phenotypic transition has emerged as a potential therapeutic strategy. Chondrocyte phenotype maintenance and switch are controlled by an intricate network of intracellular factors, each influenced by a myriad of feedback mechanisms, making it challenging to intuitively predict treatment outcomes, while in silico modeling can help unravel that complexity. In this study, we aim to develop a virtual articular chondrocyte to guide experiments in order to rationalize the identification of potential drug targets via screening of combination therapies through computational modeling and simulations. RESULTS We developed a signal transduction network model using knowledge-based and data-driven (machine learning) modeling technologies. The in silico high-throughput screening of (pairwise) perturbations operated with that network model highlighted conditions potentially affecting the hypertrophic switch. A selection of promising combinations was further tested in a murine cell line and primary human chondrocytes, which notably highlighted a previously unreported synergistic effect between the protein kinase A and the fibroblast growth factor receptor 1. CONCLUSIONS Here, we provide a virtual articular chondrocyte in the form of a signal transduction interactive knowledge base and of an executable computational model. Our in silico-in vitro strategy opens new routes for developing osteoarthritis targeting therapies by refining the early stages of drug target discovery.
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Affiliation(s)
- Raphaëlle Lesage
- Prometheus, Division of Skeletal Tissue Engineering, KU Leuven, Leuven, Belgium
- Biomechanics Section, KU Leuven, Leuven, Belgium
| | - Mauricio N Ferrao Blanco
- Department of Orthopaedics and Sports Medicine, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
| | - Roberto Narcisi
- Department of Orthopaedics and Sports Medicine, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
| | - Tim Welting
- Orthopedic Surgery Department, UMC+, Maastricht, the Netherlands
| | - Gerjo J V M van Osch
- Department of Orthopaedics and Sports Medicine, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
- Department of Otorhinolaryngology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
- Department of Biomechanical Engineering, Delft University of Technology, Delft, the Netherlands
| | - Liesbet Geris
- Prometheus, Division of Skeletal Tissue Engineering, KU Leuven, Leuven, Belgium.
- Biomechanics Section, KU Leuven, Leuven, Belgium.
- GIGA In silico Medicine, University of Liège, Liège, Belgium.
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13
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Gao L, Wang X, Xiong J, Ma Y. Circular RNA from phosphodiesterase 4D can attenuate chondrocyte apoptosis and matrix degradation under OA milieu induced by IL-1β via circPDE4D/miR-4306/SOX9 cascade. Immunopharmacol Immunotoxicol 2022; 44:682-692. [PMID: 35549803 DOI: 10.1080/08923973.2022.2077215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
BACKGROUND Phosphodiesterase 4D (PDE4D) is a novel molecular therapeutic agent for human diseases, including Alzheimer's disease, ischemic stroke, asthma and cancers. Circular RNA from PDE4D (circPDE4D; ID hsa_circ_0072568) was one of the most downregulated circRNAs in OA patients. However, its precise role in OA-related chondrocytes was largely unknown. METHODS Expressions of circPDE4D, microRNA (miR)-4306 and sex-determining region Y-box 9 (SOX9) were measured by quantitative real-time PCR; protein levels of SOX9 and proteins related to apoptosis and extracellular matrix (ECM) were detected by western blotting. Cell apoptosis was assessed by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, 5-ethynyl-2'-deoxyuridine and Annexin V-fluorescein isothiocyanate apoptosis assays. MiR-4306 response elements were predicted by bioinformatics algorithm and identified using dual-luciferase reporter, RNA immunoprecipitation and biotin-coupled miRNA capture assays. RESULTS CircPDE4D was markedly downregulated in OA cartilages and interleukin (IL)-1β-stressed human normal chondrocytes (HNC). Ectopic expression of circPDE4D rescued cell viability, proliferation, and expressions of B-cell lymphoma/leukemia-2 (Bcl-2) and Collagen type II α1 in IL-1β-insulted HNC, and meanwhile declined apoptosis rate and levels of Bcl-2-associated X protein, cleaved caspase-3, cleaved poly (ADP-ribose) polymerase-1, matrix metalloproteinase-13, ADAM metallopeptidase with thrombospondin type 1 motif 5, IL-6, and IL-8. CircPDE4D and SOX9 were competing endogenous RNAs (ceRNAs) for miR-4306, and circPDE4D could positively regulate SOX9 expression via miR-4306. CONCLUSION CircPDE4D and miR-4306 were important regulators in regulating IL-1β-induced HNC apoptosis and matrix degradation via regulating the key transcription factor SOX9, suggesting a novel circPDE4D/miR-4306/SOX9 ceRNA pathway in OA-related chondrocyte dysfunction.
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Affiliation(s)
- Lixia Gao
- Department of Rehabilitation Medicine, Wuhan First Hospital, No. 215 Zhongshan Avenue, Qiaokou District, Wuhan, Hubei, China. 430022
| | - Xiaoyun Wang
- Department of Rehabilitation Medicine, Wuhan First Hospital, No. 215 Zhongshan Avenue, Qiaokou District, Wuhan, Hubei, China. 430022
| | - Jian Xiong
- Department of Rehabilitation Medicine, Wuhan First Hospital, No. 215 Zhongshan Avenue, Qiaokou District, Wuhan, Hubei, China. 430022
| | - Yan Ma
- Department of Rehabilitation Medicine, Wuhan First Hospital, No. 215 Zhongshan Avenue, Qiaokou District, Wuhan, Hubei, China. 430022
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14
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Ren E, Chen H, Qin Z, Guan S, Jiang L, Pang X, He Y, Zhang Y, Gao X, Chu C, Zheng L, Liu G. Harnessing Bifunctional Ferritin with Kartogenin Loading for Mesenchymal Stem Cell Capture and Enhancing Chondrogenesis in Cartilage Regeneration. Adv Healthc Mater 2022; 11:e2101715. [PMID: 34997700 DOI: 10.1002/adhm.202101715] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 12/27/2021] [Indexed: 12/19/2022]
Abstract
Methods that leverage bone marrow mesenchymal stem cells (BMSCs) and stimulating factor kartogenin (KGN) for chondrocyte differentiation have paved the way for cartilage repair. However, the scarce carriers for efficiently bridging the two components significantly impede their further application. Therefore, one kind of bifunctional ferritin has designed and synthesized: RC-Fn, a genetically engineered ferritin nanocage with RGD peptide and WYRGRL peptide on the surface. The RGD can target the integrin αvβ3 of BMSCs and promote proliferation, and the WYRGRL peptide has an inherent affinity for the cartilage matrix component of collagen II protein. RC-Fn nanocages have an ideal size for penetrating the proteoglycan network of cartilage. Thus, intra-articularly injected RC-Fn with KGN loading can convert the articular cavity from a barrier into a reservoir to prevent rapid release and clearance of KGN and exogenous BMSCs, which results in efficient and persistent chondrogenesis in cartilage regeneration.
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Affiliation(s)
- En Ren
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & Center for Molecular Imaging and Translational Medicine, School of Public Health Xiamen Xiamen University Xiamen 361102 China
| | - Haimin Chen
- Guangxi Engineering Center in Biomedical Materials for Tissue and Organ Regeneration Guangxi Medical University Nanning 530021 China
| | - Zainen Qin
- Guangxi Engineering Center in Biomedical Materials for Tissue and Organ Regeneration Guangxi Medical University Nanning 530021 China
- Collaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application The First Affiliated Hospital of Guangxi Medical University Nanning 530021 China
| | - Siwen Guan
- Guangxi Engineering Center in Biomedical Materials for Tissue and Organ Regeneration Guangxi Medical University Nanning 530021 China
| | - Lai Jiang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & Center for Molecular Imaging and Translational Medicine, School of Public Health Xiamen Xiamen University Xiamen 361102 China
| | - Xin Pang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & Center for Molecular Imaging and Translational Medicine, School of Public Health Xiamen Xiamen University Xiamen 361102 China
| | - Yi He
- Guangxi Engineering Center in Biomedical Materials for Tissue and Organ Regeneration Guangxi Medical University Nanning 530021 China
| | - Yang Zhang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & Center for Molecular Imaging and Translational Medicine, School of Public Health Xiamen Xiamen University Xiamen 361102 China
| | - Xing Gao
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & Center for Molecular Imaging and Translational Medicine, School of Public Health Xiamen Xiamen University Xiamen 361102 China
| | - Chengchao Chu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & Center for Molecular Imaging and Translational Medicine, School of Public Health Xiamen Xiamen University Xiamen 361102 China
- Eye Institute of Xiamen University Fujian Provincial Key Laboratory of Ophthalmology and Visual Science Xiamen University Xiamen 361102 China
| | - Li Zheng
- Guangxi Engineering Center in Biomedical Materials for Tissue and Organ Regeneration Guangxi Medical University Nanning 530021 China
- Collaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application The First Affiliated Hospital of Guangxi Medical University Nanning 530021 China
| | - Gang Liu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & Center for Molecular Imaging and Translational Medicine, School of Public Health Xiamen Xiamen University Xiamen 361102 China
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15
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Liao HJ, Chang CH, Huang CYF, Chen HT. Potential of Using Infrapatellar–Fat–Pad–Derived Mesenchymal Stem Cells for Therapy in Degenerative Arthritis: Chondrogenesis, Exosomes, and Transcription Regulation. Biomolecules 2022; 12:biom12030386. [PMID: 35327578 PMCID: PMC8945217 DOI: 10.3390/biom12030386] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 02/23/2022] [Accepted: 02/25/2022] [Indexed: 02/04/2023] Open
Abstract
Infrapatellar fat pad–derived mesenchymal stem cells (IPFP-MSCs) are a type of adipose-derived stem cell (ADSC). They potentially contribute to cartilage regeneration and modulation of the immune microenvironment in patients with osteoarthritis (OA). The ability of IPFP-MSCs to increase chondrogenic capacity has been reported to be greater, less age dependent, and less affected by inflammatory changes than that of other MSCs. Transcription-regulatory factors strictly regulate the cartilage differentiation of MSCs. However, few studies have explored the effect of transcriptional factors on IPFP-MSC-based neocartilage formation, cartilage engineering, and tissue functionality during and after chondrogenesis. Instead of intact MSCs, MSC-derived extracellular vesicles could be used for the treatment of OA. Furthermore, exosomes are increasingly being considered the principal therapeutic agent in MSC secretions that is responsible for the regenerative and immunomodulatory functions of MSCs in cartilage repair. The present study provides an overview of advancements in enhancement strategies for IPFP-MSC chondrogenic differentiation, including the effects of transcriptional factors, the modulation of released exosomes, delivery mechanisms for MSCs, and ethical and regulatory points concerning the development of MSC products. This review will contribute to the understanding of the IPFP-MSC chondrogenic differentiation process and enable the improvement of IPFP-MSC-based cartilage tissue engineering.
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Affiliation(s)
- Hsiu-Jung Liao
- Department of Orthopedic Surgery, Far Eastern Memorial Hospital, New Taipei City 220216, Taiwan;
| | - Chih-Hung Chang
- Department of Orthopedic Surgery, Far Eastern Memorial Hospital, New Taipei City 220216, Taiwan;
- Graduate School of Biotechnology and Bioengineering, Yuan Ze University, Taoyuan City 320315, Taiwan
- Correspondence: (C.-H.C.); (H.-T.C.)
| | - Chi-Ying F. Huang
- Department of Biotechnology and Laboratory Science in Medicine, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan;
- Institute of Biopharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan
| | - Hui-Ting Chen
- Department of Pharmacy, School of Pharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan
- Department of Fragrance and Cosmetic Science, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
- School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
- Correspondence: (C.-H.C.); (H.-T.C.)
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16
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Noncanonical roles of p53 in cancer stemness and their implications in sarcomas. Cancer Lett 2022; 525:131-145. [PMID: 34742870 DOI: 10.1016/j.canlet.2021.10.037] [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: 06/06/2021] [Revised: 09/24/2021] [Accepted: 10/25/2021] [Indexed: 12/25/2022]
Abstract
Impairment of the prominent tumor suppressor p53, well known for its canonical role as the "guardian of the genome", is found in almost half of human cancers. More recently, p53 has been suggested to be a crucial regulator of stemness, orchestrating the differentiation of embryonal and adult stem cells, suppressing reprogramming into induced pluripotent stem cells, or inhibiting cancer stemness (i.e., cancer stem cells, CSCs), which underlies the development of therapy-resistant tumors. This review addresses these noncanonical roles of p53 and their implications in sarcoma initiation and progression. Indeed, dysregulation of p53 family proteins is a common event in sarcomas and is associated with poor survival. Additionally, emerging studies have demonstrated that loss of wild-type p53 activity hinders the terminal differentiation of mesenchymal stem cells and leads to the development of aggressive sarcomas. This review summarizes recent findings on the roles of aberrant p53 in sarcoma development and stemness and further describes therapeutic approaches to restore normal p53 activity as a promising anti-CSC strategy to treat refractory sarcomas.
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17
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Sałówka A, Martinez-Sanchez A. Molecular Mechanisms of Nutrient-Mediated Regulation of MicroRNAs in Pancreatic β-cells. Front Endocrinol (Lausanne) 2021; 12:704824. [PMID: 34803905 PMCID: PMC8600252 DOI: 10.3389/fendo.2021.704824] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Accepted: 08/02/2021] [Indexed: 12/12/2022] Open
Abstract
Pancreatic β-cells within the islets of Langerhans respond to rising blood glucose levels by secreting insulin that stimulates glucose uptake by peripheral tissues to maintain whole body energy homeostasis. To different extents, failure of β-cell function and/or β-cell loss contribute to the development of Type 1 and Type 2 diabetes. Chronically elevated glycaemia and high circulating free fatty acids, as often seen in obese diabetics, accelerate β-cell failure and the development of the disease. MiRNAs are essential for endocrine development and for mature pancreatic β-cell function and are dysregulated in diabetes. In this review, we summarize the different molecular mechanisms that control miRNA expression and function, including transcription, stability, posttranscriptional modifications, and interaction with RNA binding proteins and other non-coding RNAs. We also discuss which of these mechanisms are responsible for the nutrient-mediated regulation of the activity of β-cell miRNAs and identify some of the more important knowledge gaps in the field.
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Affiliation(s)
| | - Aida Martinez-Sanchez
- Section of Cell Biology and Functional Genomics, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, United Kingdom
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18
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Burgos M, Hurtado A, Jiménez R, Barrionuevo FJ. Non-Coding RNAs: lncRNAs, miRNAs, and piRNAs in Sexual Development. Sex Dev 2021; 15:335-350. [PMID: 34614501 DOI: 10.1159/000519237] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Accepted: 08/09/2021] [Indexed: 11/19/2022] Open
Abstract
Non-coding RNAs (ncRNAs) are a group of RNAs that do not encode functional proteins, including long non-coding RNAs (lncRNAs), microRNAs (miRNAs), PIWI-interacting RNAs (piRNAs), and short interfering RNAs (siRNAs). In the last 2 decades an effort has been made to uncover the role of ncRNAs during development and disease, and nowadays it is clear that these molecules have a regulatory function in many of the developmental and physiological processes where they have been studied. In this review, we provide an overview of the role of ncRNAs during gonad determination and development, focusing mainly on mammals, although we also provide information from other species, in particular when there is not much information on the function of particular types of ncRNAs during mammalian sexual development.
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Affiliation(s)
- Miguel Burgos
- Departamento de Genética e Instituto de Biotecnología, Lab. 127, Centro de Investigación Biomédica, Universidad de Granada, Granada, Spain
| | - Alicia Hurtado
- Epigenetics and Sex Development Group, Berlin Institute for Medical Systems Biology, Max-Delbrück Center for Molecular Medicine, Berlin, Germany
| | - Rafael Jiménez
- Departamento de Genética e Instituto de Biotecnología, Lab. 127, Centro de Investigación Biomédica, Universidad de Granada, Granada, Spain
| | - Francisco J Barrionuevo
- Departamento de Genética e Instituto de Biotecnología, Lab. 127, Centro de Investigación Biomédica, Universidad de Granada, Granada, Spain
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19
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The Interaction between microRNAs and the Wnt/β-Catenin Signaling Pathway in Osteoarthritis. Int J Mol Sci 2021; 22:ijms22189887. [PMID: 34576049 PMCID: PMC8470786 DOI: 10.3390/ijms22189887] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Revised: 09/07/2021] [Accepted: 09/09/2021] [Indexed: 12/14/2022] Open
Abstract
Osteoarthritis (OA) is a chronic disease affecting the whole joint, which still lacks a disease-modifying treatment. This suggests an incomplete understanding of underlying molecular mechanisms. The Wnt/β-catenin pathway is involved in different pathophysiological processes of OA. Interestingly, both excessive stimulation and suppression of this pathway can contribute to the pathogenesis of OA. microRNAs have been shown to regulate different cellular processes in different diseases, including the metabolic activity of chondrocytes and osteocytes. To bridge these findings, here we attempt to give a conclusive overview of microRNA regulation of the Wnt/β-catenin pathway in bone and cartilage, which may provide insights to advance the development of miRNA-based therapeutics for OA treatment.
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20
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Conservation of Zebrafish MicroRNA-145 and Its Role during Neural Crest Cell Development. Genes (Basel) 2021; 12:genes12071023. [PMID: 34209401 PMCID: PMC8306979 DOI: 10.3390/genes12071023] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Revised: 06/24/2021] [Accepted: 06/28/2021] [Indexed: 02/06/2023] Open
Abstract
The neural crest is a multipotent cell population that develops from the dorsal neural fold of vertebrate embryos in order to migrate extensively and differentiate into a variety of tissues. A number of gene regulatory networks coordinating neural crest cell specification and differentiation have been extensively studied to date. Although several publications suggest a common role for microRNA-145 (miR-145) in molecular reprogramming for cell cycle regulation and/or cellular differentiation, little is known about its role during in vivo cranial neural crest development. By modifying miR-145 levels in zebrafish embryos, abnormal craniofacial development and aberrant pigmentation phenotypes were detected. By whole-mount in situ hybridization, changes in expression patterns of col2a1a and Sry-related HMG box (Sox) transcription factors sox9a and sox9b were observed in overexpressed miR-145 embryos. In agreement, zebrafish sox9b expression was downregulated by miR-145 overexpression. In silico and in vivo analysis of the sox9b 3′UTR revealed a conserved potential miR-145 binding site likely involved in its post-transcriptional regulation. Based on these findings, we speculate that miR-145 participates in the gene regulatory network governing zebrafish chondrocyte differentiation by controlling sox9b expression.
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21
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Chen L, Xu J, Lv S, Zhao Y, Sun D, Zheng Y, Li X, Zhang L, Chi G, Li Y. Overexpression of long non-coding RNA AP001505.9 inhibits human hyaline chondrocyte dedifferentiation. Aging (Albany NY) 2021; 13:11433-11454. [PMID: 33839696 PMCID: PMC8109079 DOI: 10.18632/aging.202833] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Accepted: 02/18/2021] [Indexed: 12/21/2022]
Abstract
Autologous chondrocyte implantation (ACI) is an effective method for treating chronic articular cartilage injury and degeneration; however, it requires large numbers of hyaline chondrocytes, and human hyaline chondrocytes often undergo dedifferentiation in vitro. Moreover, although long non-coding RNAs (lncRNAs) regulate gene expression in many pathological and physiological processes, their role in human hyaline chondrocyte dedifferentiation remains unclear. Here, we examined lncRNA and mRNA expression profiles in human hyaline chondrocyte dedifferentiation using microarray analysis. Among the many lncRNAs and mRNAs that showed differential expression, lncRNA AP001505.9 (ENST00000569966) was significantly downregulated in chondrocytes after dedifferentiation. We next performed gene ontology, pathway, and CNC (coding-non-coding gene co-expression) analyses to investigate potential regulatory mechanisms for AP001505.9. Pellet cultures were then used to redifferentiate dedifferentiated chondrocytes, and AP001505.9 expression was upregulated after redifferentiation. Finally, both in vitro and in vivo experiments demonstrated that AP001505.9 overexpression inhibited dedifferentiation of chondrocytes. This study characterizes lncRNA expression profiles in human hyaline chondrocyte dedifferentiation, thereby identifying new potential mechanisms of chondrocyte dedifferentiation worthy of further investigation.
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Affiliation(s)
- Lin Chen
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, Jilin, China.,Department of Gastrointestinal and Colorectal Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin, China
| | - Jinying Xu
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, Jilin, China
| | - Shuang Lv
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, Jilin, China
| | - Yan Zhao
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, Jilin, China.,Department of Operating Room, China-Japan Union Hospital of Jilin University, Changchun, Jilin, China
| | - Dongjie Sun
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, Jilin, China
| | - Yangyang Zheng
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, Jilin, China
| | - Xianglan Li
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, Jilin, China.,Department of Dermatology, China-Japan Union Hospital of Jilin University, Changchun, Jilin, China
| | - Lihong Zhang
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, Jilin, China
| | - Guangfan Chi
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, Jilin, China
| | - Yulin Li
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, Jilin, China
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Lu J, Zhou Z, Sun B, Han B, Fu Q, Han Y, Yuan W, Xu Z, Chen A. MiR-520d-5p modulates chondrogenesis and chondrocyte metabolism through targeting HDAC1. Aging (Albany NY) 2020; 12:18545-18560. [PMID: 32950972 PMCID: PMC7585120 DOI: 10.18632/aging.103831] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Accepted: 07/14/2020] [Indexed: 02/07/2023]
Abstract
MicroRNAs (miRNAs) play an essential role in the chondrogenesis and the progression of osteoarthritis (OA). This study aimed to determine miRNAs associated with chondrogenesis of human mesenchymal stem cells (hMSCs) and chondrocyte metabolism. MiRNAs were screened in hMSCs during chondrogenesis by RNA-seq and qRT-PCR. MiRNA expression was determined in primary human chondrocytes (PHCs), and degraded cartilage samples. MiRNA mimics and inhibitors were transfected to cells to determine the effect of miRNA. Bioinformatic analysis and luciferase reporter assays were applied to determine the target gene of miRNA. The results demonstrated that miR-520d-5p was increased in hMSCs chondrogenesis. The overexpression and knockdown of miR-520d-5p promoted and inhibited chondrogenesis, and regulated chondrocyte metabolism. Histone deacetylase 1 (HDAC1) was decreased in hMSCs chondrogenesis, and HDAC1 was a targeting gene of miR-520d-5p. CI994, HDAC1 inhibitor, elevated cartilage-specific gene expressions and promoted hMSCs chondrogenesis. In IL-1β-treated PHCs, CI994 promoted AGGRECAN expression and suppressed MMP-13 expression, abolishing the effect of IL-1β on PHCs. Taken together, these results suggest that miR-520d-5p promotes hMSCs chondrogenesis and regulates chondrocyte metabolism through targeting HDAC1. This study provides novel understanding of the molecular mechanism of OA progression.
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Affiliation(s)
- Jiajia Lu
- Department of Orthopedics and Trauma Surgery, Changzheng Hospital, Shanghai, P. R. of China
| | - Zhibin Zhou
- Department of Orthopedics and Trauma Surgery, Changzheng Hospital, Shanghai, P. R. of China
| | - Bin Sun
- Department of Orthopedics and Trauma Surgery, Changzheng Hospital, Shanghai, P. R. of China
| | - Bin Han
- Department of Orthopedics and Trauma Surgery, Changzheng Hospital, Shanghai, P. R. of China
| | - Qiang Fu
- Department of Orthopedics and Trauma Surgery, Changzheng Hospital, Shanghai, P. R. of China
| | - Yaguang Han
- Department of Orthopedics and Trauma Surgery, Changzheng Hospital, Shanghai, P. R. of China
| | - Wang Yuan
- Department of Medicinal and Materials, General Hospital of Northern Theater Command, Shenyang, P. R. of China
| | - Zeng Xu
- Department of Orthopedics and Trauma Surgery, Changzheng Hospital, Shanghai, P. R. of China
| | - Aimin Chen
- Department of Orthopedics and Trauma Surgery, Changzheng Hospital, Shanghai, P. R. of China
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23
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Lv S, Xu J, Chen L, Wu H, Feng W, Zheng Y, Li P, Zhang H, Zhang L, Chi G, Li Y. MicroRNA-27b targets CBFB to inhibit differentiation of human bone marrow mesenchymal stem cells into hypertrophic chondrocytes. Stem Cell Res Ther 2020; 11:392. [PMID: 32917285 PMCID: PMC7488425 DOI: 10.1186/s13287-020-01909-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 08/09/2020] [Accepted: 08/27/2020] [Indexed: 12/15/2022] Open
Abstract
Background Human bone marrow-derived mesenchymal stem cells (hBMSCs) have chondrocyte differentiation potential and are considered to be a cell source for cell-transplantation-mediated repair of cartilage defects, including those associated with osteoarthritis (OA). However, chondrocyte hypertrophic differentiation is a major obstacle for the application of hBMSCs in articular cartilage defect treatment. We have previously shown that microRNA-27b (miR-27b) inhibits hypertrophy of chondrocytes from rat knee cartilage. In this study, we investigated the role of miR-27b in chondrocyte hypertrophic differentiation of hBMSCs. Methods Chondrogenic marker and microRNA expression in hBMSC chondrogenic pellets were evaluated using RT-qPCR and immunohistochemistry. The hBMSCs were transfected with miR-27b before inducing differentiation. Gene and protein expression levels were analyzed using RT-qPCR and western blot. Coimmunoprecipitation was used to confirm interaction between CBFB and RUNX2. Luciferase reporter assays were used to demonstrate that CBFB is a miR-27b target. Chondrogenic differentiation was evaluated in hBMSCs treated with shRNA targeting CBFB. Chondrogenic hBMSC pellets overexpressing miR-27b were implanted into cartilage lesions in model rats; therapeutic effects were assessed based on histology and immunohistochemistry. Results The hBMSCs showed typical MSC differentiation potentials. During chondrogenic differentiation, collagen 2 and 10 (COL2 and COL10), SOX9, and RUNX2 expression was upregulated. Expression of miR-140, miR-143, and miR-181a increased over time, whereas miR-27b and miR-221 were downregulated. Cartilage derived from hBMSC and overexpressing miR-27b exhibited higher expression of COL2 and SOX9, but lower expression of COL10, RUNX2, and CBFB than did the control cartilage. CBFB and RUNX2 formed a complex, and CBFB was identified as a novel miR-27b target. CBFB knockdown by shRNA during hBMSC chondrogenic differentiation led to significantly increased COL2 and SOX9 expression and decreased COL10 expression. Finally, miR-27b-overexpressing hBMSC chondrogenic pellets had better hyaline cartilage morphology and reduced expression of hypertrophic markers and tend to increase repair efficacy in vivo. Conclusion MiR-27b plays an important role in preventing hypertrophic chondrogenesis of hBMSCs by targeting CBFB and is essential for maintaining a hyaline cartilage state. This study provides new insights into the mechanism of hBMSC chondrocyte differentiation and will aid in the development of strategies for treating cartilage injury based on hBMSC transplantation.
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Affiliation(s)
- Shuang Lv
- The Key Laboratory of Pathobiology, Ministry of Education, Department of Pathology, College of Basic Medical Sciences, Jilin University, Changchun, 130021, China
| | - Jinying Xu
- The Key Laboratory of Pathobiology, Ministry of Education, Department of Pathology, College of Basic Medical Sciences, Jilin University, Changchun, 130021, China
| | - Lin Chen
- The Key Laboratory of Pathobiology, Ministry of Education, Department of Pathology, College of Basic Medical Sciences, Jilin University, Changchun, 130021, China.,Department of Gastrointestinal Surgery, Sino-Japanese Friendship Hospital of Jilin University, Changchun, 130021, China
| | - Haitao Wu
- The Key Laboratory of Pathobiology, Ministry of Education, Department of Pathology, College of Basic Medical Sciences, Jilin University, Changchun, 130021, China.,Department of Oncology, the First Hospital of Jilin University, Changchun, 130021, China
| | - Wei Feng
- Department of Bone and Joint, the First Hospital of Jilin University, Changchun, 130021, China
| | - Yangyang Zheng
- The Key Laboratory of Pathobiology, Ministry of Education, Department of Pathology, College of Basic Medical Sciences, Jilin University, Changchun, 130021, China
| | - Pengdong Li
- The Key Laboratory of Pathobiology, Ministry of Education, Department of Pathology, College of Basic Medical Sciences, Jilin University, Changchun, 130021, China
| | - Haiying Zhang
- The Key Laboratory of Pathobiology, Ministry of Education, Department of Pathology, College of Basic Medical Sciences, Jilin University, Changchun, 130021, China
| | - Lihong Zhang
- The Key Laboratory of Pathobiology, Ministry of Education, Department of Pathology, College of Basic Medical Sciences, Jilin University, Changchun, 130021, China
| | - Guangfan Chi
- The Key Laboratory of Pathobiology, Ministry of Education, Department of Pathology, College of Basic Medical Sciences, Jilin University, Changchun, 130021, China.
| | - Yulin Li
- The Key Laboratory of Pathobiology, Ministry of Education, Department of Pathology, College of Basic Medical Sciences, Jilin University, Changchun, 130021, China.
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24
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Zhang M, Yuan SZ, Sun H, Sun L, Zhou D, Yan J. miR-199b-5p promoted chondrogenic differentiation of C3H10T1/2 cells by regulating JAG1. J Tissue Eng Regen Med 2020; 14:1618-1629. [PMID: 32870569 DOI: 10.1002/term.3122] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 07/17/2020] [Accepted: 08/26/2020] [Indexed: 12/13/2022]
Abstract
Mesenchymal stem cells (MSCs) are considered a promising candidate for use in cell-based therapy for cartilage repair. To promote understanding of the molecular control of chondrogenesis differentiation in MSCs, we compared the changes in microRNAs during in vitro chondrogenesis process of human bone-marrow mesenchymal stem cells (hBMSCs). MiR-199b-5p was up-regulated significantly during this process. The aim of the study was to investigate the effects of miR-199b-5p on chondrogenic differentiation of C3H10T1/2 MSC cells and explore the underlying mechanisms. MiR-199b-5p mimics or inhibitor were transfected into C3H10T1/2 cells, respectively, and then, the effects of miR-199b-5p on chondrogenic differentiation of C3H10T1/2 cells were detected. The results indicated that miR-199b-5p overexpression inhibited the growth of C3H10T1/2 cells but promoted transforming growth factor-β3 (TGF-β3)-induced C3H10T1/2 cells of chondrogenic differentiation, as supported by enhancing the gene and protein expression of chondrocyte specific markers of SOX9, aggrecan, and collagen type II (Col2a1). In contrast, inhibiting miR-199b-5p notably promoted the proliferation of C3H10T1/2 cells but decreased chondrogenic differentiation. Furthermore, mechanism studies revealed that JAG1 was a direct target of miR-199b-5p by dual luciferase reporter assays. While silencing of JAG1 by isRNA resulted an increase of chondrogenic differentiation. Further, JAG1 knockdown was demonstrated to block the effect of miR-199b-5p inhibition. In conclusion, the present study revealed for the first time that miR-199b-5p was the positive regulators to modulate chondrogenic differentiation of C3H10T1/2 cells by targeting JAG1. These findings may provide a novel insight on miRNA-mediated MSC therapy for cartilage related disorders.
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Affiliation(s)
- Miao Zhang
- Department of Histology and Embryology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Shu Zheng Yuan
- Department of Histology and Embryology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Haimei Sun
- Department of Histology and Embryology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Lei Sun
- Musculosketetal Tissue Bank, Beijing Jishuitan Hospital, Beijing, China
| | - Deshan Zhou
- Department of Histology and Embryology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Jihong Yan
- Department of Histology and Embryology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
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25
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Antunes J, Lee O, Alizadeh AH, LaMarre J, Koch TG. Why the hype - What are microRNAs and why do they provide unique investigative, diagnostic, and therapeutic opportunities in veterinary medicine? THE CANADIAN VETERINARY JOURNAL = LA REVUE VETERINAIRE CANADIENNE 2020; 61:845-852. [PMID: 32741990 PMCID: PMC7350063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
MicroRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression by inhibiting translation or inducing transcript degradation. MiRNAs act as fine-tuning factors that affect the expression of up to 60% of all mammalian protein coding genes. In contrast to proteins, there is widespread conservation of miRNA sequences across species. This conservation strongly suggests that miRNAs appeared early in evolution and have retained their functional importance. Cross-species conservation provides advantages when compiling candidate markers for health and disease compared to protein-based discoveries. This broad utility is accompanied by the emergence of inexpensive sequencing protocols for the identification of all RNAs in a sample (including miRNAs). With the use of miRNA mimics and antagonists, unique research questions can be answered in biological systems with 'cause and effect' methodology. MiRNAs are readily detectable in blood making them attractive candidates as biomarkers for disease. Here, we review their utility as biomarkers and their potential as therapeutic agents or targets to combat disease.
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Affiliation(s)
- Joshua Antunes
- Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, 50 Stone Road East, Guelph, Ontario N1G 2W1
| | - Olivia Lee
- Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, 50 Stone Road East, Guelph, Ontario N1G 2W1
| | - Amir Hamed Alizadeh
- Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, 50 Stone Road East, Guelph, Ontario N1G 2W1
| | - Jonathan LaMarre
- Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, 50 Stone Road East, Guelph, Ontario N1G 2W1
| | - Thomas Gadegaard Koch
- Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, 50 Stone Road East, Guelph, Ontario N1G 2W1
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26
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Bourebaba L, Röcken M, Marycz K. Osteochondritis dissecans (OCD) in Horses - Molecular Background of its Pathogenesis and Perspectives for Progenitor Stem Cell Therapy. Stem Cell Rev Rep 2020; 15:374-390. [PMID: 30796679 PMCID: PMC6534522 DOI: 10.1007/s12015-019-09875-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Osteochondrosis (osteochondrosis dissecans; OCD) is a disease syndrome of growing cartilage related to different clinical entities such as epiphysitis, subchondral cysts and angular carpal deformities, which occurs in growing animals of all species, including horses. Nowadays, these disorders are affecting increasing numbers of young horses worldwide. As a complex multifactorial disease, OCD is initiated when failure in cartilage canals because of existing ischemia, chondrocyte biogenesis impairment as well as biochemical and genetic disruptions occur. Recently, particular attention have been accorded to the definition of possible relations between OCD and some metabolic disorders; in this way, implication of mitochondrial dysfunctions, endoplasmic reticulum disruptions, oxidative stress or endocrinological affections are among the most considered axes for future researches. As one of the most frequent cause of impaired orthopaedic potential, which may result in a sharp decrease in athletic performances of the affected animals, and lead to the occurrence of complications such as joint fragility and laminitis, OCD remains as one of the primary causes of considerable economic losses in all sections of the equine industry. It would therefore be important to provide more information on the exact pathophysiological mechanism(s) underlying early OC(D) lesions, in order to implement innovative strategies involving the use of progenitor stem cells, which are considered nowadays as a promising approach to regenerative medicine, with the potential to treat numerous orthopaedic disorders, including osteo-degenerative diseases, for prevention and reduction of incidence of the disease, not only in horses, but also in human medicine, as the equine model is already widely accepted by the scientific community and approved by the FDA, for the research and application of cellular therapies in the treatment of human conditions.
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Affiliation(s)
- Lynda Bourebaba
- Department of Experimental Biology, Faculty of Biology and Animal Science, Wrocław University of Environmental and Life Sciences, Norwida 27B, 50-375, Wrocław, Poland
| | - Michael Röcken
- Faculty of Veterinary Medicine, Equine Clinic - Equine Surgery, Justus-Liebig-University, 35392, Gießen, Germany
| | - Krzysztof Marycz
- Department of Experimental Biology, Faculty of Biology and Animal Science, Wrocław University of Environmental and Life Sciences, Norwida 27B, 50-375, Wrocław, Poland. .,Faculty of Veterinary Medicine, Equine Clinic - Equine Surgery, Justus-Liebig-University, 35392, Gießen, Germany.
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27
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Kim DH, Lee HS, Mun YH, Koh S, Park JS, Lee SM, Kang NW, Lee MY, Cho CW, Kim DD, Lee JY. An overview of chondrosarcoma with a focus on nanoscale therapeutics. JOURNAL OF PHARMACEUTICAL INVESTIGATION 2020. [DOI: 10.1007/s40005-020-00492-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
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28
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Wang J, Guo X, Kang Z, Qi L, Yang Y, Wang J, Xu J, Gao S. Roles of Exosomes from Mesenchymal Stem Cells in Treating Osteoarthritis. Cell Reprogram 2020; 22:107-117. [PMID: 32364765 DOI: 10.1089/cell.2019.0098] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Affiliation(s)
- Jian Wang
- East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xuanxuan Guo
- East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Zhanrong Kang
- Department of Orthopaedics, Shanghai Pudong Hospital, Fudan University, Shanghai, China
| | - Lingbin Qi
- Department of Regenerative Medicine, Tongji University School of Medicine, Shanghai, China
| | - Ying Yang
- Key Lab of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Ministry of Public Health, Shanghai, China
| | - Juan Wang
- Department of Cell Engineering, Binzhou Medical College, Yantai, China
| | - Jun Xu
- East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Shane Gao
- East Hospital, Tongji University School of Medicine, Shanghai, China
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29
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Urdinez J, Boro A, Mazumdar A, Arlt MJ, Muff R, Botter SM, Bode-Lesniewska B, Fuchs B, Snedeker JG, Gvozdenovic A. The miR-143/145 Cluster, a Novel Diagnostic Biomarker in Chondrosarcoma, Acts as a Tumor Suppressor and Directly Inhibits Fascin-1. J Bone Miner Res 2020; 35:1077-1091. [PMID: 32027760 DOI: 10.1002/jbmr.3976] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Revised: 01/24/2020] [Accepted: 01/29/2020] [Indexed: 12/17/2022]
Abstract
Chondrosarcoma is the second most frequent bone sarcoma. Due to the inherent chemotherapy and radiotherapy resistance and absence of known therapeutic targets, clinical management is limited to surgical resection. Consequently, patients with advanced disease face a poor prognosis. Hence, elucidating regulatory networks governing chondrosarcoma pathogenesis is vital for development of effective therapeutic strategies. Here, miRNA and mRNA next generation sequencing of different subtypes of human chondrogenic tumors in combination with in silico bioinformatics tools were performed with the aim to identify key molecular factors. We identified miR-143/145 cluster levels to inversely correlate with tumor grade. This deregulation was echoed in the miRNA plasma levels of patients and we provided the first evidence that circulating miR-145 is a potential noninvasive diagnostic biomarker and can be valuable as an indicator to improve the currently challenging diagnosis of cartilaginous bone tumors. Additionally, artificial upregulation of both miRNAs impelled a potent tumor suppressor effect in vitro and in vivo in an orthotopic xenograft mouse model. A combined in silico/sequencing approach revealed FSCN1 as a direct target of miR-143/145, and its depletion phenotypically resembled miR-143/145 upregulation in vitro. Last, FSCN1 is a malignancy-promoting factor associated with aggressive chondrosarcoma progression. Our findings underscore miR-143/145/FSCN1 as important players in chondrosarcoma and may potentially open new avenues for specific therapeutic intervention options. © 2020 American Society for Bone and Mineral Research.
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Affiliation(s)
- Joaquin Urdinez
- Department of Orthopedics, Balgrist University Hospital, Zurich, Switzerland.,Institute for Biomechanics, ETH Zurich, Zurich, Switzerland
| | - Aleksandar Boro
- Department of Orthopedics, Balgrist University Hospital, Zurich, Switzerland
| | - Alekhya Mazumdar
- Department of Orthopedics, Balgrist University Hospital, Zurich, Switzerland.,Institute for Biomechanics, ETH Zurich, Zurich, Switzerland
| | - Matthias Je Arlt
- Department of Orthopedics, Balgrist University Hospital, Zurich, Switzerland.,Institute for Biomechanics, ETH Zurich, Zurich, Switzerland
| | - Roman Muff
- Department of Orthopedics, Balgrist University Hospital, Zurich, Switzerland
| | - Sander M Botter
- Department of Orthopedics, Balgrist University Hospital, Zurich, Switzerland.,Institute for Biomechanics, ETH Zurich, Zurich, Switzerland
| | - Beata Bode-Lesniewska
- Institute for Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland
| | - Bruno Fuchs
- Department of Orthopedics, Balgrist University Hospital, Zurich, Switzerland
| | - Jess G Snedeker
- Department of Orthopedics, Balgrist University Hospital, Zurich, Switzerland.,Institute for Biomechanics, ETH Zurich, Zurich, Switzerland
| | - Ana Gvozdenovic
- Department of Orthopedics, Balgrist University Hospital, Zurich, Switzerland.,Institute for Biomechanics, ETH Zurich, Zurich, Switzerland
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30
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High-Throughput Identification of MiR-145 Targets in Human Articular Chondrocytes. Life (Basel) 2020; 10:life10050058. [PMID: 32403239 PMCID: PMC7281014 DOI: 10.3390/life10050058] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 04/30/2020] [Accepted: 05/05/2020] [Indexed: 02/06/2023] Open
Abstract
MicroRNAs (miRNAs) play key roles in cartilage development and homeostasis and are dysregulated in osteoarthritis. MiR-145 modulation induces profound changes in the human articular chondrocyte (HAC) phenotype, partially through direct repression of SOX9. Since miRNAs can simultaneously silence multiple targets, we aimed to identify the whole targetome of miR-145 in HACs, critical if miR-145 is to be considered a target for cartilage repair. We performed RIP-seq (RNA-immunoprecipitation and high-throughput sequencing) of miRISC (miRNA-induced silencing complex) in HACs overexpressing miR-145 to identify miR-145 direct targets and used cWords to assess enrichment of miR-145 seed matches in the identified targets. Further validations were performed by RT-qPCR, Western immunoblot, and luciferase assays. MiR-145 affects the expression of over 350 genes and directly targets more than 50 mRNAs through the 3′UTR or, more commonly, the coding region. MiR-145 targets DUSP6, involved in cartilage organization and development, at the translational level. DUSP6 depletion leads to MMP13 upregulation, suggesting a contribution towards the effect of miR-145 on MMP13 expression. In conclusion, miR-145 directly targets several genes involved in the expression of the extracellular matrix and inflammation in primary chondrocytes. Thus, we propose miR-145 as an important regulator of chondrocyte function and a new target for cartilage repair.
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31
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Song H, Park KH. Regulation and function of SOX9 during cartilage development and regeneration. Semin Cancer Biol 2020; 67:12-23. [PMID: 32380234 DOI: 10.1016/j.semcancer.2020.04.008] [Citation(s) in RCA: 124] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Revised: 09/23/2019] [Accepted: 04/26/2020] [Indexed: 12/21/2022]
Abstract
Chondrogenesis is a highly coordinated event in embryo development, adult homeostasis, and repair of the vertebrate cartilage. Fate decisions and differentiation of chondrocytes accompany differential expression of genes critical for each step of chondrogenesis. SOX9 is a master transcription factor that participates in sequential events in chondrogenesis by regulating a series of downstream factors in a stage-specific manner. SOX9 either works alone or in combination with downstream SOX transcription factors, SOX5 and SOX6 as chondrogenic SOX Trio. SOX9 is reduced in the articular cartilage of patients with osteoarthritis while highly maintained during tumorigenesis of cartilage and bone. Gene therapy using viral and non-viral vectors accompanied by tissue engineering (scaffolds) is a promising tool to regenerate impaired cartilage. Delivery of SOX9 or chondrogenic SOX Trio into cells produces efficient therapeutic effects on chondrogenesis and this event is facilitated by scaffolds. Non-viral vector-guided delivery systems encapsulated or loaded in mechanically stable solid scaffolds are useful for the regeneration of articular cartilage. Here we review major milestones and most recent studies focusing on regulation and function of chondrogenic SOX Trio, during chondrogenesis and cartilage regeneration, and on the development of advanced technologies in gene delivery with tissue engineering to improve efficiency of cartilage repair process.
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Affiliation(s)
- Haengseok Song
- Department of Biomedical Science, CHA University, Seongnam, Republic of Korea
| | - Keun-Hong Park
- Department of Biomedical Science, CHA University, Seongnam, Republic of Korea.
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Akaraphutiporn E, Sunaga T, Bwalya EC, Echigo R, Okumura M. Alterations in characteristics of canine articular chondrocytes in non-passaged long-term monolayer culture: Matter of differentiation, dedifferentiation and redifferentiation. J Vet Med Sci 2020; 82:793-803. [PMID: 32350166 PMCID: PMC7324834 DOI: 10.1292/jvms.20-0118] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
This study investigated the effects of culture time on phenotype stability of canine
articular chondrocytes (CACs) in non-passaged long-term monolayer culture. Third passage
(P3) CACs isolated from four cartilage samples were seeded at three different initial
seeding densities (0.2 × 104, 1.0 × 104 and 5.0 × 104
cells/cm2) and maintained in monolayer condition up to 8 weeks without
undergoing subculture after confluence. The characteristic changes of chondrocytes during
the culture period were evaluated based on the cell morphology, cell proliferation,
glycosaminoglycans (GAGs) content, DNA quantification, mRNA expression and ultrastructure
of chondrocytes. Chondrocytes maintained under post-confluence condition exhibited a
capability to grow and proliferate up to 4 weeks. Alcian blue staining and
Dimethylmethylene blue (DMMB) assay revealed that the extracellular matrix (ECM) synthesis
was increased in a time-dependent manner from 2 to 8 weeks. The chondrocyte mRNA
expression profile was dramatically affected by prolonged culture time, with a significant
downregulation of collagen type I, whereas the expression of
collagen type II, aggrecan, Sox9 and
matrix metalloproteinase 13 (MMP-13) were significantly upregulated. In
addition, transmission electron microscopy (TEM) result indicated dilation of rough
endoplasmic reticulum (RER) in these long-term monolayer cultured chondrocytes. These
findings demonstrate that the chondrocytes phenotype could be partially redifferentiated
through the spontaneous redifferentiation process in long-term cultures using standard
culture medium without the addition of chondrogenic supplements or tissue-culture
scaffolds.
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Affiliation(s)
- Ekkapol Akaraphutiporn
- Laboratory of Veterinary Surgery, Department of Veterinary Clinical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido 060-0818, Japan
| | - Takafumi Sunaga
- Laboratory of Veterinary Surgery, Department of Veterinary Clinical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido 060-0818, Japan
| | - Eugene C Bwalya
- Department of Clinical Studies, Samora Machel School of Veterinary Medicine, University of Zambia, Lusaka 10101, Zambia
| | - Ryosuke Echigo
- Veterinary Medical Teaching Hospital, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido 060-0818, Japan
| | - Masahiro Okumura
- Laboratory of Veterinary Surgery, Department of Veterinary Clinical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido 060-0818, Japan
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Harsanyi S, Zamborsky R, Krajciova L, Kokavec M, Danisovic L. Developmental Dysplasia of the Hip: A Review of Etiopathogenesis, Risk Factors, and Genetic Aspects. MEDICINA (KAUNAS, LITHUANIA) 2020; 56:153. [PMID: 32244273 PMCID: PMC7230892 DOI: 10.3390/medicina56040153] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Revised: 03/25/2020] [Accepted: 03/28/2020] [Indexed: 12/11/2022]
Abstract
As one of the most frequent skeletal anomalies, developmental dysplasia of the hip (DDH) is characterized by a considerable range of pathology, from minor laxity of ligaments in the hip joint to complete luxation. Multifactorial etiology, of which the candidate genes have been studied the most, poses a challenge in understanding this disorder. Candidate gene association studies (CGASs) along with genome-wide association studies (GWASs) and genome-wide linkage analyses (GWLAs) have found numerous genes and loci with susceptible DDH association. Studies put major importance on candidate genes associated with the formation of connective tissue (COL1A1), osteogenesis (PAPPA2, GDF5), chondrogenesis (UQCC1, ASPN) and cell growth, proliferation and differentiation (TGFB1). Recent studies show that epigenetic factors, such as DNA methylation affect gene expression and therefore could play an important role in DDH pathogenesis. This paper reviews all existing risk factors affecting DDH incidence, along with candidate genes associated with genetic or epigenetic etiology of DDH in various studies.
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Affiliation(s)
- Stefan Harsanyi
- Faculty of Medicine, Institute of Medical Biology, Genetics and Clinical Genetics, Comenius University in Bratislava, 811-08 Bratislava, Slovakia; (L.K.); (L.D.)
| | - Radoslav Zamborsky
- Department of Orthopedics, Faculty of Medicine, Comenius University and National Institute of Children’s Diseases, 833-40 Bratislava, Slovakia; (R.Z.); (M.K.)
| | - Lubica Krajciova
- Faculty of Medicine, Institute of Medical Biology, Genetics and Clinical Genetics, Comenius University in Bratislava, 811-08 Bratislava, Slovakia; (L.K.); (L.D.)
| | - Milan Kokavec
- Department of Orthopedics, Faculty of Medicine, Comenius University and National Institute of Children’s Diseases, 833-40 Bratislava, Slovakia; (R.Z.); (M.K.)
| | - Lubos Danisovic
- Faculty of Medicine, Institute of Medical Biology, Genetics and Clinical Genetics, Comenius University in Bratislava, 811-08 Bratislava, Slovakia; (L.K.); (L.D.)
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Griffiths R, Woods S, Cheng A, Wang P, Griffiths-Jones S, Ronshaugen M, Kimber SJ. The Transcription Factor-microRNA Regulatory Network during hESC-chondrogenesis. Sci Rep 2020; 10:4744. [PMID: 32179818 PMCID: PMC7075910 DOI: 10.1038/s41598-020-61734-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Accepted: 02/19/2020] [Indexed: 12/21/2022] Open
Abstract
Human embryonic stem cells (ESCs) offer a promising therapeutic approach for osteoarthritis (OA). The unlimited source of cells capable of differentiating to chondrocytes has potential for repairing damaged cartilage or to generate disease models via gene editing. However their use is limited by the efficiency of chondrogenic differentiation. An improved understanding of the transcriptional and post-transcriptional regulation of chondrogenesis will enable us to improve hESC chondrogenic differentiation protocols. Small RNA-seq and whole transcriptome sequencing was performed on distinct stages of hESC-directed chondrogenesis. This revealed significant changes in the expression of several microRNAs including upregulation of known cartilage associated microRNAs and those transcribed from the Hox complexes, and the downregulation of pluripotency associated microRNAs. Integration of miRomes and transcriptomes generated during hESC-directed chondrogenesis identified key functionally related clusters of co-expressed microRNAs and protein coding genes, associated with pluripotency, primitive streak, limb development and extracellular matrix. Analysis identified regulators of hESC-directed chondrogenesis such as miR-29c-3p with 10 of its established targets identified as co-regulated 'ECM organisation' genes and miR-22-3p which is highly co-expressed with ECM genes and may regulate these genes indirectly by targeting the chondrogenic regulators SP1 and HDAC4. We identified several upregulated transcription factors including HOXA9/A10/D13 involved in limb patterning and RELA, JUN and NFAT5, which have targets enriched with ECM associated genes. We have developed an unbiased approach for integrating transcriptome and miRome using protein-protein interactions, transcription factor regulation and miRNA target interactions and identified key regulatory networks prominent in hESC chondrogenesis.
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Affiliation(s)
- Rosie Griffiths
- Divisions of Cell Matrix Biology and Regenerative Medicine, Faculty of Biology Medicine and Health, Michael Smith Building, Oxford Road, University of Manchester, Manchester Academic Health Science Centre, Manchester, M13 9PT, UK
- Centre for Discovery Brain Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD, United Kingdom
| | - Steven Woods
- Divisions of Cell Matrix Biology and Regenerative Medicine, Faculty of Biology Medicine and Health, Michael Smith Building, Oxford Road, University of Manchester, Manchester Academic Health Science Centre, Manchester, M13 9PT, UK
| | - Aixin Cheng
- Divisions of Cell Matrix Biology and Regenerative Medicine, Faculty of Biology Medicine and Health, Michael Smith Building, Oxford Road, University of Manchester, Manchester Academic Health Science Centre, Manchester, M13 9PT, UK
- Salford Royal NHS Foundation Trust, Department of Trauma and Orthopaedic, Stott Lane, Salford, M6 8HD, United Kingdom
| | - Ping Wang
- Evolution and Genomic Science, Faculty of Biology Medicine and Health, Michael Smith Building, Oxford Road, University of Manchester, Manchester Academic Health Science Centre, Manchester, M13 9PT, UK
| | - Sam Griffiths-Jones
- Evolution and Genomic Science, Faculty of Biology Medicine and Health, Michael Smith Building, Oxford Road, University of Manchester, Manchester Academic Health Science Centre, Manchester, M13 9PT, UK
| | - Matthew Ronshaugen
- Developmental Biology and Medicine, Faculty of Biology Medicine and Health, Michael Smith Building, Oxford Road, University of Manchester, Manchester Academic Health Science Centre, Manchester, M13 9PT, UK
| | - Susan J Kimber
- Divisions of Cell Matrix Biology and Regenerative Medicine, Faculty of Biology Medicine and Health, Michael Smith Building, Oxford Road, University of Manchester, Manchester Academic Health Science Centre, Manchester, M13 9PT, UK.
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Sun P, Wu Y, Li X, Jia Y. miR-142-5p protects against osteoarthritis through competing with lncRNA XIST. J Gene Med 2020; 22:e3158. [PMID: 31903636 DOI: 10.1002/jgm.3158] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Revised: 01/03/2020] [Accepted: 01/03/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND The relevance between abnormal microRNA expression and osteoarthritis (OA) has been elaborated in recent studies. Hence, the present study aimed to assess the impact of miR-142-5p on chondrocyte growth and apoptosis. METHODS To mimic OA-like chondrocyte damage, interleukin (IL)-1β was used for chondrocyte treatment. The expression of miR-142-5p, SGTB, long non-coding RNA (lncRNA) X inactive specific transcript (XIST) and involved molecules such as Col2A1, Bcl-2, MMP13 and Bax was determined via a quantitative reverse transcriptase-polymerase chain reaction and western blot analyses. Functional roles of miR-142-5p, SGTB and XIST were monitored in 5-ethynyl-2'-deoxyuridine, CCK-8 and TUNEL experiments. Rescue analyses were conducted to consolidate the effect of the XIST/miR-142-5p/SGTB axis on chondrocytes in OA. RESULTS miR-142-5p was down-regulated in IL-1β-treated chondrocytes, whereas SGTB and XIST levels were increased. Overexpression of miR-142-5p stimulated proliferation and retarded apoptosis in IL-1β-treated chondrocytes. Meanwhile, miR-142-5p elevation was correlated with an elevation of Col2A1 and Bcl-2, as well as a decline of MMP13 and Bax. A mechanistic study showed that miR-142-5p negatively regulated SGTB expression. Moreover, we found that lncRNA XIST could relieve the inhibition of miR-142-5p on SGTB expression. Augmentation of SGTB or suppression of miR-142-5p reversed the influence of XIST depletion on chondrocyte growth and apoptosis. CONCLUSIONS The present study has explored the fundamental role of miR-142-5p in IL-1β-treated chondrocytes, as well as the novel molecular mechanism constituted by miR-142-5p/SGTB/XIST in OA. Potentially, the results obtained may add new insight into OA pathogenesis.
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Affiliation(s)
- Pengfei Sun
- Department of Orthopedics, Qilu Hospital of Shandong University, Jinan, China
| | - Yunpeng Wu
- Department of Orthopedics, Qilu Hospital of Shandong University, Jinan, China
| | - Xuezhou Li
- Department of Orthopedics, Qilu Hospital of Shandong University, Jinan, China
| | - Yuhua Jia
- Department of Orthopedics, Qilu Hospital of Shandong University, Jinan, China
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Ishikawa S, Iijima K, Matsukuma D, Iijima M, Osawa S, Otsuka H. Enhanced function of chondrocytes in a chitosan‐based hydrogel to regenerate cartilage tissues by accelerating degradability of the hydrogel via a hydrolysable crosslinker. J Appl Polym Sci 2019. [DOI: 10.1002/app.48893] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Affiliation(s)
- Shohei Ishikawa
- Department of Science, Graduate School of Chemical SciencesTokyo University of Science, 1‐3 Kagurazaka, Shinjuku‐ku Tokyo 162‐8601 Japan
| | - Kazutoshi Iijima
- Department of Industrial Chemistry, Faculty of EngineeringTokyo University of Science, 12‐1 Ichigayafunagawara‐machi, Shinjuku‐ku Tokyo 162‐0826 Japan
| | - Daisuke Matsukuma
- Department of Applied Chemistry, Faculty of ScienceTokyo University of Science, 1‐3 Kagurazaka, Shinjuku‐ku Tokyo 162‐8601 Japan
| | - Michihiro Iijima
- Department of Materials Chemistry and BioengineeringOyama National College of Technology, 771 Nakakuki, Oyama Tochigi 323‐0806 Japan
| | - Shigehito Osawa
- Department of Applied Chemistry, Faculty of ScienceTokyo University of Science, 1‐3 Kagurazaka, Shinjuku‐ku Tokyo 162‐8601 Japan
| | - Hidenori Otsuka
- Department of Science, Graduate School of Chemical SciencesTokyo University of Science, 1‐3 Kagurazaka, Shinjuku‐ku Tokyo 162‐8601 Japan
- Department of Industrial Chemistry, Faculty of EngineeringTokyo University of Science, 12‐1 Ichigayafunagawara‐machi, Shinjuku‐ku Tokyo 162‐0826 Japan
- Water Frontier Science & Technology Research CenterResearch Institute for Science and Technology, Tokyo University of Science Shinjuku‐ku Tokyo 162‐8601 Japan
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Chen D, Kim DJ, Shen J, Zou Z, O'Keefe RJ. Runx2 plays a central role in Osteoarthritis development. J Orthop Translat 2019; 23:132-139. [PMID: 32913706 PMCID: PMC7452174 DOI: 10.1016/j.jot.2019.11.008] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Revised: 11/21/2019] [Accepted: 11/25/2019] [Indexed: 12/20/2022] Open
Abstract
Osteoarthritis (OA) is the most common form of arthritis, is the leading cause of impaired mobility in the elderly, and accounts for more than a third of chronic moderate to severe pain. As a degenerative joint disorder, OA affects the whole joint and results in synovial hyperplasia, degradation of articular cartilage, subchondral sclerosis, osteophyte formation, and chronic pain. Currently, there is no effective drug to decelerate OA progression and molecular targets for drug development have been insufficiently investigated. Anti-OA drug development can benefit from more and precise knowledge of molecular targets for drug development. Runt-related transcription factor 2 (Runx2) is a key transcription factor controlling osteoblast and chondrocyte differentiation and is among the most promising potential therapeutic targets. Notably, Runx2 expression is upregulated in several murine OA models, suggesting a role in disease pathogenesis. In this review article, we summarized recent findings on Runx2 related to OA development and evaluated its potential as a therapeutic target. The translational potential of this article A better understanding of the role of Runx2 in osteoarthritis pathogenesis will contribute to the development of novel intervention of osteoarthritis disease.
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Affiliation(s)
- Di Chen
- Research Center for Human Tissues and Organs Degeneration, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
| | - Dongyeon J Kim
- Department of Orthopedic Surgery, Washington University at St. Louis, MO, USA
| | - Jie Shen
- Department of Orthopedic Surgery, Washington University at St. Louis, MO, USA
| | - Zhen Zou
- Department of Orthopedic Surgery, Washington University at St. Louis, MO, USA
| | - Regis J O'Keefe
- Department of Orthopedic Surgery, Washington University at St. Louis, MO, USA
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Tangredi BP, Lawler DF. Osteoarthritis from evolutionary and mechanistic perspectives. Anat Rec (Hoboken) 2019; 303:2967-2976. [PMID: 31854144 DOI: 10.1002/ar.24339] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2019] [Revised: 10/15/2019] [Accepted: 11/11/2019] [Indexed: 12/21/2022]
Abstract
Developmental osteogenesis and the pathologies associated with tissues that normally are mineralized are active areas of research. All of the basic cell types of skeletal tissue evolved in early aquatic vertebrates. Their characteristics, transcription factors, and signaling pathways have been conserved, even as they adapted to the challenge imposed by gravity in the transition to terrestrial existence. The response to excess mechanical stress (among other factors) can be expressed in the pathologic phenotype described as osteoarthritis (OA). OA is mediated by epigenetic modification of the same conserved developmental gene networks, rather than by gene mutations or new chemical signaling pathways. Thus, these responses have their evolutionary roots in morphogenesis. Epigenetic channeling and heterochrony, orchestrated primarily by microRNAs, maintain the sequence of these responses, while allowing variation in their timing that depends at least partly on the life history of the individual.
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Affiliation(s)
- Basil P Tangredi
- Vermont Institute of Natural Sciences, Quechee, Vermont
- Sustainable Agriculture Program, Green Mountain College, Poultney, Vermont
| | - Dennis F Lawler
- Center for American Archaeology, Kampsville, Illinois
- Illinois State Museum, Springfield, Illinois
- Pacific Marine Mammal Center, Laguna Beach, California
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Melatonin Prevents Osteoarthritis-Induced Cartilage Degradation via Targeting MicroRNA-140. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:9705929. [PMID: 31915516 PMCID: PMC6935446 DOI: 10.1155/2019/9705929] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Revised: 11/17/2019] [Accepted: 11/28/2019] [Indexed: 12/21/2022]
Abstract
Osteoarthritis (OA) is characterized by the progressive destruction of articular cartilage, which is involved in the imbalance between extracellular matrix (ECM) synthesis and degradation. MicroRNA-140-5p (miR-140) is specifically expressed in cartilage and plays an important role in OA-induced matrix degradation. The aim of this study was to investigate (1) whether intra-articular injection of melatonin could ameliorate surgically induced OA in mice and (2) whether melatonin could regulate matrix-degrading enzymes at the posttranscriptional level by targeting miR-140. In an in vitro OA environment induced by interleukin-1 beta (IL-1β), melatonin treatment improved cell proliferation of human chondrocytes, promoted the expression of cartilage ECM proteins (e.g., type II collagen and aggrecan), and inhibited the levels of IL-1β-induced proteinases, such as matrix metalloproteinase 9 (MMP9), MMP13, ADAMTS4 (a disintegrin and metalloproteinase with thrombospondin motifs 4), and ADAMTS5. Both the microarray and polymerase chain reaction (PCR) experiments revealed that miR-140 was a melatonin-responsive microRNA and melatonin upregulated miR-140 expression, which was suppressed by IL-1β stimulation. In vivo experiments demonstrated that intra-articular injection of melatonin prevented disruptions of cartilage matrix homeostasis and successfully alleviated the progression of surgery-induced OA in mice. Transfection of miR-140 antagomir completely counteracted the antiarthritic effects of melatonin by promoting matrix destruction. Our findings demonstrate that melatonin protects the articular cartilage from OA-induced degradation by targeting miR-140, and intra-articular administration of melatonin may benefit patients suffering from OA.
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Liu C, Ren S, Zhao S, Wang Y. LncRNA MALAT1/MiR-145 Adjusts IL-1β-Induced Chondrocytes Viability and Cartilage Matrix Degradation by Regulating ADAMTS5 in Human Osteoarthritis. Yonsei Med J 2019; 60:1081-1092. [PMID: 31637891 PMCID: PMC6813144 DOI: 10.3349/ymj.2019.60.11.1081] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Revised: 08/02/2019] [Accepted: 08/14/2019] [Indexed: 12/21/2022] Open
Abstract
PURPOSE Accumulating evidence suggests that microRNA-145 (miR-145) plays an important role in osteoarthritis (OA), which is a chronic progressive joint disease. Long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) promotes metastasis in cancers and functions as a sponge for miR-145. However, the role of MALAT1/miR-145 in OA pathogenesis has not yet been elucidated. MATERIALS AND METHODS The expression of MALAT1 and miR-145 was examined by quantitative real-time PCR; the interaction between miR-145, MALAT1 and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) 5 was verified by luciferase reporter assay. Correlations among MALAT1, miR-145, and ADAMTS5 were analyzed by Spearman rank analysis. Chondrocytes viability and cartilage extracellular matrix (ECM) degradation were investigated with cell viability assay and Western blotting analyzing expression of ADAMTS5, collagen type 2 alpha 1 (COL2A1), aggrecan (ACAN), and cartilage oligomeric matrix protein (COMP). RESULTS MALAT1 was upregulated, and miR-145 was downregulated in OA samples and IL-1β-induced chondrocytes. Mechanically, miR-145 could directly bind to MALAT1 and ADAMTS5. Moreover, miR-145 expression was negatively correlated with MALAT1 and ADAMTS5 expression in OA patients, whereas MALAT1 and ADAMTS5 expression was positively correlated. Functionally, overexpression of MALAT1 inhibited chondrocyte viability and promoted cartilage ECM degradation in IL-1β-induced chondrocytes. In support thereof, MALAT1 silencing and miR-145 upregulation exerted the opposite effect in IL-1β-induced chondrocytes. Moreover, the effect of MALAT1 was counteracted by miR-145 upregulation, and ADAMTS5 restoration could abate miR-145 effects. CONCLUSION An MALAT1/miR-145 axis contributes to ECM degradation in IL-1β-induced chondrocytes through targeting ADAMTS5, suggesting that MALAT1/miR-145/ADAMTS5 signaling may underlie human OA pathogenesis.
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Affiliation(s)
- Chengyao Liu
- Department of Bone and Joint Surgery, The Sixth People's Hospital of Ji'nan City (Zhangqiu People's Hospital affiliated to Jining Medical University), Shandong, China
| | - Shan Ren
- Department of Bone and Joint Surgery, The Sixth People's Hospital of Ji'nan City (Zhangqiu People's Hospital affiliated to Jining Medical University), Shandong, China
| | - Shifeng Zhao
- Department of Dermatology, The Sixth People's Hospital of Ji'nan City (Zhangqiu People's Hospital affiliated to Jining Medical University), Shandong, China
| | - Yandong Wang
- Department of Orthopedics, the Forth Hospital of Yulin (Xingyuan Hospital), West Yulin, Shaanxi, China.
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Tankyrase inhibition preserves osteoarthritic cartilage by coordinating cartilage matrix anabolism via effects on SOX9 PARylation. Nat Commun 2019; 10:4898. [PMID: 31653858 PMCID: PMC6814715 DOI: 10.1038/s41467-019-12910-2] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2018] [Accepted: 10/07/2019] [Indexed: 01/31/2023] Open
Abstract
Osteoarthritis (OA) is a prevalent degenerative disease, which involves progressive and irreversible destruction of cartilage matrix. Despite efforts to reconstruct cartilage matrix in osteoarthritic joints, it has been a difficult task as adult cartilage exhibits marginal repair capacity. Here we report the identification of tankyrase as a regulator of the cartilage anabolism axis based on systems-level factor analysis of mouse reference populations. Tankyrase inhibition drives the expression of a cartilage-signature matrisome and elicits a transcriptomic pattern that is inversely correlated with OA progression. Furthermore, tankyrase inhibitors ameliorate surgically induced OA in mice, and stem cell transplantation coupled with tankyrase knockdown results in superior regeneration of cartilage lesions. Mechanistically, the pro-regenerative features of tankyrase inhibition are mainly triggered by uncoupling SOX9 from a poly(ADP-ribosyl)ation (PARylation)-dependent protein degradation pathway. Our findings provide insights into the development of future OA therapies aimed at reconstruction of articular cartilage. Osteoarthritis results from the progressive destruction of cartilage matrix. Here, Kim et al. identify tankyrase as a regulator of cartilage matrix anabolism, and find that tankyrase inhibition, by preventing SOX9 PARylation, protects from cartilage destruction in a mouse model of osteoarthritis.
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Nasr MA, Salah RA, Abd Elkodous M, Elshenawy SE, El-Badri N. Dysregulated MicroRNA Fingerprints and Methylation Patterns in Hepatocellular Carcinoma, Cancer Stem Cells, and Mesenchymal Stem Cells. Front Cell Dev Biol 2019; 7:229. [PMID: 31681762 PMCID: PMC6811506 DOI: 10.3389/fcell.2019.00229] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Accepted: 09/26/2019] [Indexed: 12/14/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the top causes of cancer mortality worldwide. Although HCC has been researched extensively, there is still a need for novel and effective therapeutic interventions. There is substantial evidence that initiation of carcinogenesis in liver cirrhosis, a leading cause of HCC, is mediated by cancer stem cells (CSCs). CSCs were also shown to be responsible for relapse and chemoresistance in several cancers, including HCC. MicroRNAs (miRNAs) constitute important epigenetic markers that regulate carcinogenesis by acting post-transcriptionally on mRNAs, contributing to the progression of HCC. We have previously shown that co-culture of cancer cells with mesenchymal stem cells (MSCs) could induce the reprogramming of MSCs into CSC-like cells. In this review, we evaluate the available data concerning the epigenetic regulation of miRNAs through methylation and the possible role of this regulation in stem cell and somatic reprogramming in HCC.
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Affiliation(s)
- Mohamed A Nasr
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, 6th of October City, Egypt
| | - Radwa Ayman Salah
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, 6th of October City, Egypt
| | - M Abd Elkodous
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, 6th of October City, Egypt
| | - Shimaa E Elshenawy
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, 6th of October City, Egypt
| | - Nagwa El-Badri
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, 6th of October City, Egypt
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Wang XZ, Li WX. Changes of serum inflammatory factors and miR-145 expression in patients with osteoarthritis before and after treatment and their clinical value. World J Clin Cases 2019; 7:2963-2975. [PMID: 31624744 PMCID: PMC6795716 DOI: 10.12998/wjcc.v7.i19.2963] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 08/09/2019] [Accepted: 08/20/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Osteoarthritis is a chronic degenerative disease with an incidence of 50% in people over 65 years old and 80% in people over 80 years old worldwide. It is the second leading reason of loss of working capacity after cardiovascular diseases and severely affects the society and families. Therefore, finding biological markers related to the diagnosis and treatment of osteoarthritis is of great significance in clinical practice.
AIM To observe the changes and clinical value of serum inflammatory factors and miR-145 expression in patients with osteoarthritis before and after treatment.
METHODS Eighty-three patients with knee osteoarthritis (observation group) who were admitted to our hospital from April 2013 to June 2015, and 60 healthy people (control group) during the same period were selected. After 4 wk of treatment, the levels of miR-145, tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-10 were compared between the control group and the observation group before treatment. The correlation of miR-145, TNF-α, IL-6, and IL-10 levels with visual analogue scale (VAS), Lysholm, and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores was assessed by Pearson correlation analysis. The correlation of the expression of miR-145, TNF-α, IL-6, and IL-10 with Kellgren-Lawrence (K-L) grades was assessed by Spearman correlation analysis. The critical levels of miR-145, TNF-α, IL-6, and IL-10 in distinguishing different K-L grades were determined by receiver operating characteristic (ROC) curve analysis.
RESULTS The expression level of miR-145 in the observation group was significantly higher than that in the control group before treatment (P < 0.05). After treatment, the expression level of miR-145 in the observation group was significantly lower than that before treatment (P < 0.05). The levels of TNF-α and IL-6 in the observation group were significantly higher than those in the control group (P < 0.05), and the level of IL-10 was significantly lower than that in the control group (P < 0.05). After treatment, the levels of TNF-α and IL-6 in the observation group were significantly lower than those before treatment (P < 0.05), and IL-I0 level was significantly higher than that before treatment (P < 0.05). VAS and WOMAC scores were both positively correlated with miR-145, TNF-α, and IL-6 (P < 0.05), and negatively correlated with IL-10 (P < 0.05), while Lysholm scores were negatively correlated with miR-145, TNF-α, and IL-6 (P < 0.05), and positively correlated with IL-10 (P < 0.05). K-L grades were positively correlated with miR-145, TNF-α, and IL-6 (P < 0.05), and negatively correlated with IL-10 (P < 0.05). The area under the ROC curve (AUC) and specificity of TNF-α in differentiating K-L grades I-II were the highest, which were 0.785 and 97.45%, respectively, and miR145 had the highest sensitivity of 94.59%; the AUC and sensitivity of IL-6 in differentiating K-L grades II-III were the highest, which were 0.766 and 97.30%, respectively, and TNF-α had the highest specificity of 86.68%.
CONCLUSION MiR-145 and inflammatory factors have certain diagnostic value in osteoarthritis, and they are expected to become potential indicators for the diagnosis and evaluation of osteoarthritis in the future.
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Affiliation(s)
- Xiao-Zhen Wang
- Department of Orthopedics, Dongying Shengli Hospital, Bei'er Road, Dongying 257055, Shandong Province, China
| | - Wen-Xue Li
- Department of Orthopedics, Dongying Shengli Hospital, Bei'er Road, Dongying 257055, Shandong Province, China
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Razmara E, Bitaraf A, Yousefi H, Nguyen TH, Garshasbi M, Cho WCS, Babashah S. Non-Coding RNAs in Cartilage Development: An Updated Review. Int J Mol Sci 2019; 20:E4475. [PMID: 31514268 PMCID: PMC6769748 DOI: 10.3390/ijms20184475] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Revised: 09/02/2019] [Accepted: 09/02/2019] [Indexed: 02/06/2023] Open
Abstract
In the development of the skeleton, the long bones are arising from the process of endochondral ossification (EO) in which cartilage is replaced by bone. This complex process is regulated by various factors including genetic, epigenetic, and environmental elements. It is recognized that DNA methylation, higher-order chromatin structure, and post-translational modifications of histones regulate the EO. With emerging understanding, non-coding RNAs (ncRNAs) have been identified as another mode of EO regulation, which is consist of microRNAs (miRNAs or miRs) and long non-coding RNAs (lncRNAs). There is expanding experimental evidence to unlock the role of ncRNAs in the differentiation of cartilage cells, as well as the pathogenesis of several skeletal disorders including osteoarthritis. Cutting-edge technologies such as epigenome-wide association studies have been employed to reveal disease-specific patterns regarding ncRNAs. This opens a new avenue of our understanding of skeletal cell biology, and may also identify potential epigenetic-based biomarkers. In this review, we provide an updated overview of recent advances in the role of ncRNAs especially focus on miRNA and lncRNA in the development of bone from cartilage, as well as their roles in skeletal pathophysiology.
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Affiliation(s)
- Ehsan Razmara
- Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran P.O. Box 14115-111, Iran
| | - Amirreza Bitaraf
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran P.O. Box 14115-111, Iran
| | - Hassan Yousefi
- Department of Biochemistry and Molecular Biology, LSUHSC School of Medicine, New Orleans, LA 70112, USA
| | - Tina H Nguyen
- Department of Biochemistry and Molecular Biology, LSUHSC School of Medicine, New Orleans, LA 70112, USA
| | - Masoud Garshasbi
- Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran P.O. Box 14115-111, Iran
| | | | - Sadegh Babashah
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran P.O. Box 14115-111, Iran.
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Lolli A, Sivasubramaniyan K, Vainieri ML, Oieni J, Kops N, Yayon A, van Osch GJVM. Hydrogel-based delivery of antimiR-221 enhances cartilage regeneration by endogenous cells. J Control Release 2019; 309:220-230. [PMID: 31369767 DOI: 10.1016/j.jconrel.2019.07.040] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2019] [Revised: 06/15/2019] [Accepted: 07/28/2019] [Indexed: 02/06/2023]
Abstract
Articular cartilage is frequently injured by trauma or osteoarthritis, with limited and inadequate treatment options. We investigated a new strategy based on hydrogel-mediated delivery of a locked nucleic acid microRNA inhibitor targeting miR-221 (antimiR-221) to guide in situ cartilage repair by endogenous cells. First, we showed that transfection of antimiR-221 into human bone marrow-derived mesenchymal stromal cells (hMSCs) blocked miR-221 expression and enhanced chondrogenesis in vitro. Next, we loaded a fibrin/hyaluronan (FB/HA) hydrogel with antimiR-221 in combination or not with lipofectamine carrier. FB/HA strongly retained functional antimiR-221 over 14 days of in vitro culture, and provided a supportive environment for cell transfection, as validated by flow cytometry and qRT-PCR analysis. Seeding of hMSCs on the surface of antimiR-221 loaded FB/HA led to invasion of the hydrogel and miR-221 knockdown in situ within 7 days. Overall, the use of lipofectamine enhanced the potency of the system, with increased antimiR-221 retention and miR-221 silencing in infiltrating cells. Finally, FB/HA hydrogels were used to fill defects in osteochondral biopsies that were implanted subcutaneously in mice. FB/HA loaded with antimiR-221/lipofectamine significantly enhanced cartilage repair by endogenous cells, demonstrating the feasibility of our approach and the need to achieve highly effective in situ transfection. Our study provides new evidence on the treatment of focal cartilage injuries using controlled biomaterial-mediated delivery of antimicroRNA for in situ guided regeneration.
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Affiliation(s)
- Andrea Lolli
- Department of Orthopaedics, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
| | | | - Maria L Vainieri
- Department of Orthopaedics, Erasmus MC, University Medical Center, Rotterdam, the Netherlands; AO Research Institute, Davos, Switzerland
| | - Jacopo Oieni
- Faculty of Biotechnology and Food Engineering, Technion - Israel Institute of Technology, Haifa, Israel
| | - Nicole Kops
- Department of Orthopaedics, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
| | - Avner Yayon
- ProCore Ltd., Weizmann Science Park, Nes Ziona, Israel
| | - Gerjo J V M van Osch
- Department of Orthopaedics, Erasmus MC, University Medical Center, Rotterdam, the Netherlands; Department of Otorhinolaryngology, Head and Neck Surgery, Erasmus MC, University Medical Center, Rotterdam, the Netherlands.
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Liu M, Zhang J, Liu W, Wang W. Salidroside protects ATDC5 cells against lipopolysaccharide-induced injury through up-regulation of microRNA-145 in osteoarthritis. Int Immunopharmacol 2019; 67:441-448. [PMID: 30586667 DOI: 10.1016/j.intimp.2018.12.041] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Revised: 12/17/2018] [Accepted: 12/17/2018] [Indexed: 01/15/2023]
Abstract
BACKGROUND Osteoarthritis (OA) is a kind of degenerative disease characterized by the degeneration of the articular cartilage. Salidroside (SAL) is an active component of Rhodiola rosea L., which exhibits diverse pharmacological effects in different diseases. However, the effects of SAL on OA remain largely unclear. The study aimed to investigate the roles of SAL in lipopolysaccharides (LPS)-induced inflammatory injury in murine ATDC5 chondrocyte cells. METHODS LPS induced ATDC5 cell injury model was constructed by determining cell viability, apoptosis, apoptosis-associated factors as well as inflammatory cytokines expressions and concentrations. Then, the various concentrations of SAL were used to treat ATDC5 cells, and the effect of SAL on LPS-induce inflammatory injury was detected. After treatment with SAL, the expression level of miR-145 was measured by qRT-PCR. Subsequently, miR-145 inhibitor and corresponding control were transfected into ATDC5 cells to explore the influences of miR-145 in LPS-induce inflammatory injury. Besides, the key signaling pathways of NF-κB and p38MAPK were analyzed by using western blot. RESULTS LPS inhibited cell viability, induced apoptosis, activated cleaved-caspase-3/-9 expression, as well as increased IL-6, MCP-1 and TNF-α expressions and secretions in ATDC5 cells. SAL significantly alleviated LPS-induced inflammatory injury. Meanwhile, the expression of miR-145 was up-regulated by SAL. The protective effect of SAL on LPS-induced injury was obviously reversed by miR-145 inhibition. Furthermore, SAL inactivated NF-κB and p38MAPK signaling pathways by regulating miR-145. CONCLUSIONS These findings suggested that SAL could protect ATDC5 cells against LPS-induced injury via up-regulation of miR-145 in ATDC5 chondrocyte cells.
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Affiliation(s)
- Meihan Liu
- Department of Ultrasonography, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin, China
| | - Jingzhe Zhang
- Department of Orthopedics, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin, China
| | - Wanguo Liu
- Department of Orthopedics, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin, China
| | - Wenjun Wang
- Department of Orthopedics, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin, China.
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Bai M, Yin H, Zhao J, Li Y, Wu Y. miR-182-5p overexpression inhibits chondrogenesis by down-regulating PTHLH. Cell Biol Int 2019; 43:222-232. [PMID: 30095215 DOI: 10.1002/cbin.11047] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Accepted: 08/05/2018] [Indexed: 12/21/2022]
Abstract
Human bone marrow mesenchymal stem cells (hBM-MSC) have the ability of differentiating into chondrocytes and osteoblasts. miR-182-5p promotes osteoclastogenesis and bone metastasis by up-regulating the expression of parathyroid hormone-like hormone (PTHLH). However, the function of miR-182-5p in chondrogenesis is still unknown. Mimic or inhibitor of miR-182-5p was used to upregulate or knock-down miR-182-5p expression, respectively. We analyzed chondrogenesis by Safranin O staining and Blyscan™ Sulfated Glycosaminoglycan Assay. Immunohistochemistry, real-time PCR, and Western bolts were used to detect related makers. miR-182-5p overexpression inhibited chondrogenesis. Dual-luciferase reporter assay indicated that PTHLH was one of the target genes of miR-182-5p. Further studies showed that miR-182-5p overexpression down-regulated the expression of SOX-9 and COL2A1, but up-regulated COL1A1 and COL10A1. Consistently, miR-182-5p knock-down had the opposite effects. This effect of miR-182-5p in BM-MSCs can be rescued by PTHLH overexpression. miR-182-5p may play a negative role in chondrogenesis by down-regulating PTHLH.
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Affiliation(s)
- Ming Bai
- Department of Minimally Invasive Spine Surgery, The Second Affiliated Hospital of Inner Mongolia Medical University, NO 1, Yingfang Road, Hohhot, Inner Mongolia 010000, P. R. China
| | - Heping Yin
- Department of Minimally Invasive Spine Surgery, The Second Affiliated Hospital of Inner Mongolia Medical University, NO 1, Yingfang Road, Hohhot, Inner Mongolia 010000, P. R. China
| | - Jian Zhao
- Department of Minimally Invasive Spine Surgery, The Second Affiliated Hospital of Inner Mongolia Medical University, NO 1, Yingfang Road, Hohhot, Inner Mongolia 010000, P. R. China
| | - Yang Li
- Department of Minimally Invasive Spine Surgery, The Second Affiliated Hospital of Inner Mongolia Medical University, NO 1, Yingfang Road, Hohhot, Inner Mongolia 010000, P. R. China
| | - Yimin Wu
- Department of Minimally Invasive Spine Surgery, The Second Affiliated Hospital of Inner Mongolia Medical University, NO 1, Yingfang Road, Hohhot, Inner Mongolia 010000, P. R. China
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Lolli A, Colella F, De Bari C, van Osch GJVM. Targeting anti-chondrogenic factors for the stimulation of chondrogenesis: A new paradigm in cartilage repair. J Orthop Res 2019; 37:12-22. [PMID: 30175861 DOI: 10.1002/jor.24136] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2018] [Accepted: 08/09/2018] [Indexed: 02/04/2023]
Abstract
Trauma and age-related cartilage disorders represent a major global cause of morbidity, resulting in chronic pain and disability in patients. A lack of effective therapies, together with a rapidly aging population, creates an impressive clinical and economic burden on healthcare systems. In this scenario, experimental therapies based on transplantation or in situ stimulation of skeletal Mesenchymal Stem/progenitor Cells (MSCs) have raised great interest for cartilage repair. Nevertheless, the challenge of guiding MSC differentiation and preventing cartilage hypertrophy and calcification still needs to be overcome. While research has mostly focused on the stimulation of cartilage anabolism using growth factors, several issues remain unresolved prompting the field to search for novel solutions. Recently, inhibition of anti-chondrogenic regulators has emerged as an intriguing opportunity. Anti-chondrogenic regulators include extracellular proteins as well as intracellular transcription factors and microRNAs that act as potent inhibitors of pro-chondrogenic signals. Suppression of these inhibitors can enhance MSC chondrogenesis and production of cartilage matrix. We here review the current knowledge concerning different types of anti-chondrogenic regulators. We aim to highlight novel therapeutic targets for cartilage repair and discuss suitable tools for suppressing their anti-chondrogenic functions. Further effort is needed to unveil the therapeutic perspectives of this approach and pave the way for effective treatment of cartilage injuries in patients. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.
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Affiliation(s)
- Andrea Lolli
- Department of Orthopaedics, Erasmus MC, University Medical Center, Wytemaweg 80, 3015CN Rotterdam, the Netherlands
| | - Fabio Colella
- Arthritis and Regenerative Medicine Laboratory, Aberdeen Centre for Arthritis and Musculoskeletal Health, Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom
| | - Cosimo De Bari
- Arthritis and Regenerative Medicine Laboratory, Aberdeen Centre for Arthritis and Musculoskeletal Health, Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom
| | - Gerjo J V M van Osch
- Department of Orthopaedics, Erasmus MC, University Medical Center, Wytemaweg 80, 3015CN Rotterdam, the Netherlands.,Department of Otorhinolaryngology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
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Wang L, Xu X, Yang J, Chen L, Liu B, Liu T, Jin Q. Integrated microRNA and mRNA analysis in the pathogenic filamentous fungus Trichophyton rubrum. BMC Genomics 2018; 19:933. [PMID: 30547762 PMCID: PMC6295003 DOI: 10.1186/s12864-018-5316-3] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Accepted: 11/27/2018] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Trichophyton rubrum (T. rubrum) is an important model organism of dermatophytes, which are the most common fungal pathogens worldwide. Despite the severity and prevalence of the infection caused by these pathogens, current therapies are not sufficient. MicroRNA (miRNA) is a class of small noncoding RNAs that are key factors in the regulation of gene expression. These miRNAs are reported to be highly conserved in different organisms and are involved in various essential cellular processes. In this study, we performed an integrated analysis of microRNA-like RNAs (milRNAs) and mRNAs between conidial and mycelial stages to investigate the roles of milRNAs in regulating the expression of target genes in T. rubrum. RESULTS A total of 158 conserved milRNAs and 12 novel milRNAs were identified in our study, corresponding to 5470 target genes, which were involved in various essential biological pathways. In addition, 137 target genes corresponding to 21 milRNAs were concurrent differentially expressed between the conidial and mycelial stages. Among these 137 target genes, 64 genes showed the opposite trend to their corresponding milRNAs in expression difference between the two stages, indicating possible negative regulation. Furthermore, 46% of differentially expressed target genes are involved in transcription, transcriptional and post-transcriptional regulation. Our results indicate that milRNAs might associate with other regulatory elements to control gene expression at both transcriptional and post-transcriptional level. CONCLUSIONS This study provides the first analysis of milRNA expression profile in T. rubrum as well as dermatophytes in general. The results revealed the roles of milRNAs in regulating gene expression between the two major growth stages of this fungus. Our study deepens our understanding of T. rubrum and will serve as a foundation for further investigations to combat this fungus.
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Affiliation(s)
- Lingling Wang
- MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Xingye Xu
- MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Jian Yang
- MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Lihong Chen
- MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Bo Liu
- MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Tao Liu
- MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
| | - Qi Jin
- MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
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