{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T21:07:48Z","timestamp":1791234468004,"version":"4.1.0"},"reference-count":86,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,8,23]],"date-time":"2021-08-23T00:00:00Z","timestamp":1629676800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005847","name":"Health and Medical Research Fund","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005847","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001839","name":"University Grants Committee","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001839","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p><jats:bold>Background:<\/jats:bold> Osteoarthritis (OA) is one of the main causes of disability in the elderly population, accompanied by a series of underlying pathologic changes, such as cartilage degradation, synovitis, subchondral bone sclerosis, and meniscus injury. The present study aimed to identify key genes, signaling pathways, and miRNAs in knee OA associated with the entire joint components, and to explain the potential mechanisms using computational analysis.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> The differentially expressed genes (DEGs) in cartilage, synovium, subchondral bone, and meniscus were identified using the Gene Expression Omnibus 2R (GEO2R) analysis based on dataset from GSE43923, GSE12021, GSE98918, and GSE51588, respectively and visualized in Volcano Plot. Venn diagram analyses were performed to identify the overlapping DEGs (overlapping DEGs) that expressed in at least two types of tissues mentioned above. Gene Ontology (GO) enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, protein-protein interaction (PPI) analysis, and module analysis were conducted. Furthermore, qRT-PCR was performed to validate above results using our clinical specimens.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> As a result, a total of 236 overlapping DEGs were identified, of which 160 were upregulated and 76 were downregulated. Through enrichment analysis and constructing the PPI network and miRNA-mRNA network, knee OA-related key genes, such as <jats:italic>HEY1<\/jats:italic>, <jats:italic>AHR<\/jats:italic>, <jats:italic>VEGFA<\/jats:italic>, <jats:italic>MYC<\/jats:italic>, and <jats:italic>CXCL12<\/jats:italic> were identified. Clinical validation by qRT-PCR experiments further supported above computational results. In addition, knee OA-related key miRNAs such as miR-101, miR-181a, miR-29, miR-9, and miR-221, and pathways such as Wnt signaling, HIF-1 signaling, PI3K-Akt signaling, and axon guidance pathways were also identified. Among above identified knee OA-related key genes, pathways and miRNAs, genes such as <jats:italic>AHR<\/jats:italic>, <jats:italic>HEY1<\/jats:italic>, <jats:italic>MYC<\/jats:italic>, <jats:italic>GAP43<\/jats:italic>, and <jats:italic>PTN<\/jats:italic>, pathways like axon guidance, and miRNAs such as miR-17, miR-21, miR-155, miR-185, and miR-1 are lack of research and worthy for future investigation.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> The present informatic study for the first time provides insight to the potential therapeutic targets of knee OA by comprehensively analyzing the overlapping genes differentially expressed in multiple joint components and their relevant signaling pathways and interactive miRNAs.<\/jats:p>","DOI":"10.3389\/fphar.2021.730587","type":"journal-article","created":{"date-parts":[[2021,8,23]],"date-time":"2021-08-23T06:43:28Z","timestamp":1629701008000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":23,"title":["Comprehensive Analysis of Key Genes, Signaling Pathways and miRNAs in Human Knee Osteoarthritis: Based on Bioinformatics"],"prefix":"10.3389","volume":"12","author":[{"given":"Liang","family":"Chang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Yao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi","family":"Yao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin Ki-Wai","family":"Ho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael Tim-Yun","family":"Ong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingyang","family":"Dai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenxue","family":"Tong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiankun","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Qin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,8,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1089\/jir.2012.0107","article-title":"Cigarette Smoke Condensate Extracts Induce IL-1-Beta Production From Rheumatoid Arthritis Patient-Derived Synoviocytes, but Not Osteoarthritis Patient-Derived Synoviocytes, Through Aryl Hydrocarbon Receptor-Dependent NF-Kappa-B Activation and Novel NF-Kappa-B Sites","volume":"33","author":"Adachi","year":"2013","journal-title":"J. Interferon Cytokine Res."},{"key":"B2","doi-asserted-by":"publisher","first-page":"18743","DOI":"10.1038\/srep18743","article-title":"Messenger RNA Delivery of a Cartilage-Anabolic Transcription Factor as a Disease-Modifying Strategy for Osteoarthritis Treatment","volume":"6","author":"Aini","year":"2016","journal-title":"Sci. Rep."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1073","DOI":"10.1136\/annrheumdis-2011-200519","article-title":"MicroRNA-199a* Regulates the Expression of Cyclooxygenase-2 in Human Chondrocytes","volume":"71","author":"Akhtar","year":"2012","journal-title":"Ann. Rheum. Dis."},{"key":"B4","doi-asserted-by":"publisher","first-page":"726","DOI":"10.1016\/j.biocel.2004.11.005","article-title":"The Serine\/threonine Kinase Pim-1","volume":"37","author":"Bachmann","year":"2005","journal-title":"Int. J. Biochem. Cel Biol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"891","DOI":"10.1136\/ard.2004.026906","article-title":"The Regulation of Human MMP-13 by Licofelone, an Inhibitor of Cyclo-Oxygenases and 5-lipoxygenase, in Human Osteoarthritic Chondrocytes Is Mediated by the Inhibition of the P38 MAP Kinase Signalling Pathway","volume":"64","author":"Boileau","year":"2005","journal-title":"Ann. Rheum. Dis."},{"key":"B6","doi-asserted-by":"publisher","first-page":"2040622319882531","DOI":"10.1177\/2040622319882531","article-title":"Stromal Cell-Derived Factor-1 as a Potential Therapeutic Target for Osteoarthritis and Rheumatoid Arthritis","volume":"10","author":"Bragg","year":"2019","journal-title":"Ther. Adv. Chronic Dis."},{"key":"B7","doi-asserted-by":"publisher","first-page":"422","DOI":"10.1016\/j.joca.2017.12.004","article-title":"Transcriptome Comparison of Meniscus from Patients With and Without Osteoarthritis","volume":"26","author":"Brophy","year":"2018","journal-title":"Osteoarthritis Cartilage."},{"key":"B8","doi-asserted-by":"publisher","first-page":"8059","DOI":"10.3390\/ijms16048059","article-title":"Expression of the Aryl Hydrocarbon Receptor in Growth Plate Cartilage and the Impact of its Local Modulation on Longitudinal Bone Growth","volume":"16","author":"Cedervall","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1036","DOI":"10.1016\/j.joca.2021.03.015","article-title":"TDP-43 Maintains Chondrocyte Homeostasis and Alleviates Cartilage Degradation in Osteoarthritis","volume":"29","author":"Chang","year":"2021","journal-title":"Osteoarthritis Cartilage."},{"key":"B10","doi-asserted-by":"publisher","first-page":"16044","DOI":"10.1038\/boneres.2016.44","article-title":"Osteoarthritis: Toward a Comprehensive Understanding of Pathological Mechanism","volume":"5","author":"Chen","year":"","journal-title":"Bone Res."},{"key":"B11","doi-asserted-by":"publisher","first-page":"986","DOI":"10.1016\/j.joca.2017.01.008","article-title":"Attenuation of Subchondral Bone Abnormal Changes in Osteoarthritis by Inhibition of SDF-1 Signaling","volume":"25","author":"Chen","year":"","journal-title":"Osteoarthritis Cartilage."},{"key":"B12","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1136\/annrheumdis-2018-214282","article-title":"Critical Role for Arginase II in Osteoarthritis Pathogenesis","volume":"78","author":"Choi","year":"2019","journal-title":"Ann. Rheum. Dis."},{"key":"B13","doi-asserted-by":"publisher","first-page":"R190","DOI":"10.1186\/ar4380","article-title":"Genome-Wide Expression Profiles of Subchondral Bone in Osteoarthritis","volume":"15","author":"Chou","year":"2013","journal-title":"Arthritis Res. Ther."},{"key":"B14","doi-asserted-by":"publisher","first-page":"8293921","DOI":"10.1155\/2020\/8293921","article-title":"The Role of Inflammation in the Pathogenesis of Osteoarthritis","volume":"2020","author":"Chow","year":"2020","journal-title":"Mediators Inflamm."},{"key":"B15","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1136\/annrheumdis-2018-213882","article-title":"RNA Sequencing Data Integration Reveals an miRNA Interactome of Osteoarthritis Cartilage","volume":"78","author":"Coutinho de Almeida","year":"2019","journal-title":"Ann. Rheum. Dis."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1331","DOI":"10.1038\/mt.2015.61","article-title":"Silencing of miR-101 Prevents Cartilage Degradation by Regulating Extracellular Matrix-Related Genes in a Rat Model of Osteoarthritis","volume":"23","author":"Dai","year":"2015","journal-title":"Mol. Ther."},{"key":"B17","doi-asserted-by":"publisher","first-page":"R1208","DOI":"10.1186\/ar1806","article-title":"Pro-Inflammatory Properties of Stromal Cell-Derived Factor-1 (CXCL12) in Collagen-Induced Arthritis","volume":"7","author":"De Klerck","year":"2005","journal-title":"Arthritis Res. Ther."},{"key":"B18","doi-asserted-by":"publisher","first-page":"943","DOI":"10.3390\/ijms17060943","article-title":"Inhibition of SDF-1\u03b1\/CXCR4 Signalling in Subchondral Bone Attenuates Post-Traumatic Osteoarthritis","volume":"17","author":"Dong","year":"2016","journal-title":"Int. J. Mol. Sci."},{"key":"B19","doi-asserted-by":"publisher","first-page":"e6425","DOI":"10.7717\/peerj.6425","article-title":"Aberrantly Hydroxymethylated Differentially Expressed Genes and the Associated Protein Pathways in Osteoarthritis","volume":"7","author":"Fang","year":"2019","journal-title":"PeerJ."},{"key":"B20","doi-asserted-by":"publisher","first-page":"713","DOI":"10.1016\/j.stemcr.2019.08.006","article-title":"Lgr5 and Col22a1 Mark Progenitor Cells in the Lineage Toward Juvenile Articular Chondrocytes","volume":"13","author":"Feng","year":"2019","journal-title":"Stem Cel Rep."},{"key":"B21","doi-asserted-by":"publisher","first-page":"1080","DOI":"10.1136\/annrheumdis-2012-201978","article-title":"Notch Signalling Pathways Mediate Synovial Angiogenesis in Response to Vascular Endothelial Growth Factor and Angiopoietin 2","volume":"72","author":"Gao","year":"2013","journal-title":"Ann. Rheum. Dis."},{"key":"B22","doi-asserted-by":"publisher","first-page":"585","DOI":"10.3389\/fendo.2019.00585","article-title":"The Role of the CXCL12\/CXCR4\/ACKR3 Axis in Autoimmune Diseases","volume":"10","author":"Garc\u00eda-Cuesta","year":"2019","journal-title":"Front. Endocrinol. (Lausanne)."},{"key":"B23","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1016\/j.bcp.2019.02.030","article-title":"Targeting Chronic Innate Inflammatory Pathways, the Main Road to Prevention of Osteoarthritis Progression","volume":"165","author":"Herrero-Beaumont","year":"2019","journal-title":"Biochem. Pharmacol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1875","DOI":"10.1073\/pnas.1207458110","article-title":"Notch Signaling in Chondrocytes Modulates Endochondral Ossification and Osteoarthritis Development","volume":"110","author":"Hosaka","year":"2013","journal-title":"Proc. Natl. Acad. Sci. U S A."},{"key":"B25","doi-asserted-by":"publisher","first-page":"4738","DOI":"10.1038\/ncomms5738","article-title":"Aryl Hydrocarbon Receptor Negatively Regulates NLRP3 Inflammasome Activity by Inhibiting NLRP3 Transcription","volume":"5","author":"Huai","year":"2014","journal-title":"Nat. Commun."},{"key":"B26","doi-asserted-by":"publisher","first-page":"D148","DOI":"10.1093\/nar\/gkz896","article-title":"miRTarBase 2020: Updates to the Experimentally Validated microRNA-Target Interaction Database","volume":"48","author":"Huang","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"B27","doi-asserted-by":"publisher","first-page":"D1013","DOI":"10.1093\/nar\/gky1010","article-title":"HMDD v3.0: a Database for Experimentally Supported Human microRNA-Disease Associations","volume":"47","author":"Huang","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"B28","doi-asserted-by":"publisher","first-page":"R98","DOI":"10.1186\/ar2485","article-title":"Identification of Intra-Group, Inter-Individual, and Gene-Specific Variances in mRNA Expression Profiles in the Rheumatoid Arthritis Synovial Membrane","volume":"10","author":"Huber","year":"2008","journal-title":"Arthritis Res. Ther."},{"key":"B29","doi-asserted-by":"publisher","first-page":"14867","DOI":"10.1073\/pnas.1111101108","article-title":"NLRP3 Inflammasome Plays a Critical Role in the Pathogenesis of Hydroxyapatite-Associated Arthropathy","volume":"108","author":"Jin","year":"2011","journal-title":"Proc. Natl. Acad. Sci. U S A."},{"key":"B30","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/j.matbio.2016.11.005","article-title":"Expression of Adipokines in Osteoarthritis Osteophytes and Their Effect on Osteoblasts","volume":"62","author":"Junker","year":"2017","journal-title":"Matrix Biol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1016\/j.jot.2021.04.009","article-title":"Differential Gene Expression Profile by RNA Sequencing Study of Elderly Osteoporotic Hip Fracture Patients with Sarcopenia","volume":"29","author":"Kang","year":"2021","journal-title":"J. Orthop. Translat."},{"key":"B32","doi-asserted-by":"publisher","first-page":"581","DOI":"10.1016\/j.joca.2009.12.002","article-title":"Genome-Wide Expression Profiling Reveals New Candidate Genes Associated with Osteoarthritis","volume":"18","author":"Karlsson","year":"2010","journal-title":"Osteoarthritis Cartilage."},{"key":"B33","doi-asserted-by":"publisher","first-page":"2978","DOI":"10.1002\/jor.24065","article-title":"Changes in Proinflammatory Cytokines, Neuropeptides, and Microglia in an Animal Model of Monosodium Iodoacetate-Induced Hip Osteoarthritis","volume":"36","author":"Kawarai","year":"2018","journal-title":"J. Orthop. Res."},{"key":"B34","doi-asserted-by":"publisher","first-page":"730","DOI":"10.1016\/j.cell.2014.01.007","article-title":"Regulation of the Catabolic Cascade in Osteoarthritis by the Zinc-ZIP8-MTF1 Axis","volume":"156","author":"Kim","year":"2014","journal-title":"Cell."},{"key":"B35","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1177\/1947603513480809","article-title":"The Transient Chondrocyte Phenotype in Human Osteophytic Cartilage: A Role of Pigment Epithelium-Derived Factor?","volume":"4","author":"Klinger","year":"2013","journal-title":"Cartilage."},{"key":"B36","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1002\/art.40378","article-title":"Cartilage MicroRNA Dysregulation during the Onset and Progression of Mouse Osteoarthritis Is Independent of Aggrecanolysis and Overlaps with Candidates From End-Stage Human Disease","volume":"70","author":"Kung","year":"2018","journal-title":"Arthritis Rheumatol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"1764","DOI":"10.1136\/annrheumdis-2017-211396","article-title":"Microarray Analysis of Bone Marrow Lesions in Osteoarthritis Demonstrates Upregulation of Genes Implicated in Osteochondral Turnover, Neurogenesis and Inflammation","volume":"76","author":"Kuttapitiya","year":"2017","journal-title":"Ann. Rheum. Dis."},{"key":"B38","doi-asserted-by":"publisher","first-page":"1708","DOI":"10.1136\/annrheumdis-2012-202639","article-title":"Aryl Hydrocarbon Receptor Antagonism Mitigates Cytokine-Mediated Inflammatory Signalling in Primary Human Fibroblast-Like Synoviocytes","volume":"72","author":"Lahoti","year":"2013","journal-title":"Ann. Rheum. Dis."},{"key":"B39","doi-asserted-by":"publisher","first-page":"673","DOI":"10.1038\/s41584-020-00518-6","article-title":"Emerging Pharmaceutical Therapies for Osteoarthritis","volume":"16","author":"Latourte","year":"2020","journal-title":"Nat. Rev. Rheumatol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1007\/s00109-015-1374-z","article-title":"The MicroRNA-29 Family in Cartilage Homeostasis and Osteoarthritis","volume":"94","author":"Le","year":"2016","journal-title":"J. Mol. Med. (Berl)."},{"key":"B41","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1016\/j.jot.2020.07.007","article-title":"Identification of Circ-Fam169a Sponges miR-583 Involved in the Regulation of Intervertebral Disc Degeneration","volume":"26","author":"Li","year":"2021","journal-title":"J. Orthop. Translat."},{"key":"B42","doi-asserted-by":"publisher","first-page":"4579","DOI":"10.1038\/s41467-019-12163-z","article-title":"HIF1\u03b1 Inhibition Facilitates Leflunomide-AHR-CRP Signaling to Attenuate Bone Erosion in CRP-Aberrant Rheumatoid Arthritis","volume":"10","author":"Liang","year":"2019","journal-title":"Nat. Commun."},{"key":"B43","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1186\/s12929-018-0410-z","article-title":"Vasoactive Intestinal Peptide Alleviates Osteoarthritis Effectively via Inhibiting NF-\u039ab Signaling Pathway","volume":"25","author":"Liang","year":"2018","journal-title":"J. Biomed. Sci."},{"key":"B44","doi-asserted-by":"publisher","first-page":"2037","DOI":"10.1136\/annrheumdis-2015-208420","article-title":"Inhibition of Notch1 Promotes Hedgehog Signalling in a HES1-Dependent Manner in Chondrocytes and Exacerbates Experimental Osteoarthritis","volume":"75","author":"Lin","year":"2016","journal-title":"Ann. Rheum. Dis."},{"key":"B45","doi-asserted-by":"publisher","first-page":"220","DOI":"10.1016\/j.jconrel.2019.07.040","article-title":"Hydrogel-Based Delivery of antimiR-221 Enhances Cartilage Regeneration by Endogenous Cells","volume":"309","author":"Lolli","year":"2019","journal-title":"J. Control. Release."},{"key":"B46","doi-asserted-by":"publisher","first-page":"3218","DOI":"10.18632\/aging.102801","article-title":"LINC00623\/miR-101\/HRAS Axis Modulates IL-1\u03b2-Mediated ECM Degradation, Apoptosis and Senescence of Osteoarthritis Chondrocytes","volume":"12","author":"L\u00fc","year":"2020","journal-title":"Aging."},{"key":"B47","doi-asserted-by":"publisher","first-page":"2117","DOI":"10.1002\/art.39173","article-title":"MicroRNA-9 Promotion of Interleukin-6 Expression by Inhibiting Monocyte Chemoattractant Protein-Induced Protein 1 Expression in Interleukin-1\u03b2-Stimulated Human Chondrocytes","volume":"67","author":"Makki","year":"2015","journal-title":"Arthritis Rheumatol."},{"key":"B48","doi-asserted-by":"publisher","first-page":"861","DOI":"10.1517\/14728222.11.7.861","article-title":"Targeting Pleiotropin to Treat Osteoarthritis","volume":"11","author":"Mentlein","year":"2007","journal-title":"Expert Opin. Ther. Targets."},{"key":"B49","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1136\/annrheumdis-2018-213629","article-title":"MicroRNA-181a-5p Antisense Oligonucleotides Attenuate Osteoarthritis in Facet and Knee Joints","volume":"78","author":"Nakamura","year":"2019","journal-title":"Ann. Rheum. Dis."},{"key":"B50","doi-asserted-by":"publisher","first-page":"20223","DOI":"10.1038\/srep20223","article-title":"Notch-Regulated miR-223 Targets the Aryl Hydrocarbon Receptor Pathway and Increases Cytokine Production in Macrophages From Rheumatoid Arthritis Patients","volume":"6","author":"Ogando","year":"2016","journal-title":"Sci. Rep."},{"key":"B51","doi-asserted-by":"publisher","first-page":"3000","DOI":"10.1002\/art.30482","article-title":"Semaphorin 3A Is Expressed in Human Osteoarthritic Cartilage and Antagonizes Vascular Endothelial Growth Factor 165-promoted Chondrocyte Migration: an Implication for Chondrocyte Cloning","volume":"63","author":"Okubo","year":"2011","journal-title":"Arthritis Rheum."},{"key":"B52","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1186\/1471-2474-12-134","article-title":"Pain-Related Sensory Innervation in Monoiodoacetate-Induced Osteoarthritis in Rat Knees That Gradually Develops Neuronal Injury in Addition to Inflammatory Pain","volume":"12","author":"Orita","year":"2011","journal-title":"BMC Musculoskelet. Disord."},{"key":"B53","doi-asserted-by":"publisher","first-page":"819","DOI":"10.1007\/s00296-016-3451-1","article-title":"Unique Gene Expression Profile in Osteoarthritis Synovium Compared With Cartilage: Analysis of Publicly Accessible Microarray Datasets","volume":"36","author":"Park","year":"2016","journal-title":"Rheumatol. Int."},{"key":"B54","doi-asserted-by":"publisher","first-page":"1878","DOI":"10.1016\/j.celrep.2019.10.018","article-title":"Aryl Hydrocarbon Receptor Contributes to the Transcriptional Program of IL-10-Producing Regulatory B Cells","volume":"29","author":"Piper","year":"2019","journal-title":"Cell Rep."},{"key":"B55","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1016\/j.abb.2019.02.008","article-title":"NOD-Like Receptors and Inflammasomes: A Review of Their Canonical and Non-Canonical Signaling Pathways","volume":"670","author":"Platnich","year":"2019","journal-title":"Arch. Biochem. Biophys."},{"key":"B56","doi-asserted-by":"publisher","first-page":"260","DOI":"10.1016\/s1063-4584(02)00385-0","article-title":"Pleiotrophin, an Embryonic Differentiation and Growth Factor, Is Expressed in Osteoarthritis","volume":"11","author":"Pufe","year":"2003","journal-title":"Osteoarthritis Cartilage."},{"key":"B57","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1016\/j.joca.2006.07.005","article-title":"Effects of Pleiotrophin, a Heparin-Binding Growth Factor, on Human Primary and Immortalized Chondrocytes","volume":"15","author":"Pufe","year":"2007","journal-title":"Osteoarthritis Cartilage."},{"key":"B58","doi-asserted-by":"publisher","first-page":"837","DOI":"10.1016\/j.cmet.2020.03.003","article-title":"Microbiota-Derived Metabolites Suppress Arthritis by Amplifying Aryl-Hydrocarbon Receptor Activation in Regulatory B Cells","volume":"31","author":"Rosser","year":"2020","journal-title":"Cell Metab."},{"key":"B59","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1038\/nrrheum.2011.199","article-title":"Etiology of Osteoarthritis: Genetics and Synovial Joint Development","volume":"8","author":"Sandell","year":"2012","journal-title":"Nat. Rev. Rheumatol."},{"key":"B60","doi-asserted-by":"publisher","first-page":"2498","DOI":"10.1101\/gr.1239303","article-title":"Cytoscape: a Software Environment for Integrated Models of Biomolecular Interaction Networks","volume":"13","author":"Shannon","year":"2003","journal-title":"Genome Res."},{"key":"B61","doi-asserted-by":"publisher","first-page":"760","DOI":"10.1136\/annrheumdis-2017-212037","article-title":"Drug-Induced Modulation of Gp130 Signalling Prevents Articular Cartilage Degeneration and Promotes Repair","volume":"77","author":"Shkhyan","year":"2018","journal-title":"Ann. Rheum. Dis."},{"key":"B62","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1136\/annrheumdis-2017-212603","article-title":"Stratification of Knee Osteoarthritis: Two Major Patient Subgroups Identified by Genome-Wide Expression Analysis of Articular Cartilage","volume":"77","author":"Soul","year":"2018","journal-title":"Ann. Rheum. Dis."},{"key":"B63","doi-asserted-by":"publisher","first-page":"1681","DOI":"10.1038\/s41588-018-0247-0","article-title":"Meta-analysis of Icelandic and UK Data Sets Identifies Missense Variants in SMO, IL11, COL11A1 and 13 More New Loci Associated With Osteoarthritis","volume":"50","author":"Styrkarsdottir","year":"2018","journal-title":"Nat. Genet."},{"key":"B64","doi-asserted-by":"publisher","first-page":"3080","DOI":"10.1073\/pnas.1419699112","article-title":"Transcription Factor Hes1 Modulates Osteoarthritis Development in Cooperation With Calcium\/Calmodulin-Dependent Protein Kinase 2","volume":"112","author":"Sugita","year":"2015","journal-title":"Proc. Natl. Acad. Sci. U S A."},{"key":"B65","doi-asserted-by":"publisher","first-page":"5703651","DOI":"10.1155\/2018\/5703651","article-title":"Semaphorin 3A Inhibits Inflammation in Chondrocytes under Excessive Mechanical Stress","volume":"2018","author":"Sumi","year":"2018","journal-title":"Mediators Inflamm."},{"key":"B66","doi-asserted-by":"publisher","first-page":"D605","DOI":"10.1093\/nar\/gkaa1074","article-title":"The STRING Database in 2021: Customizable Protein-Protein Networks, and Functional Characterization of User-Uploaded Gene\/measurement Sets","volume":"49","author":"Szklarczyk","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"B67","doi-asserted-by":"publisher","first-page":"2761","DOI":"10.1158\/0008-5472.CAN-10-0402","article-title":"Repression of Vascular Endothelial Growth Factor Expression by the Runt-Related Transcription Factor 1 in Acute Myeloid Leukemia","volume":"71","author":"Ter Elst","year":"2011","journal-title":"Cancer Res."},{"key":"B68","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1038\/jid.2011.194","article-title":"Identification of Ketoconazole as an AhR-Nrf2 Activator in Cultured Human Keratinocytes: the Basis of its Anti-inflammatory Effect","volume":"132","author":"Tsuji","year":"2012","journal-title":"J. Invest. Dermatol."},{"key":"B69","doi-asserted-by":"publisher","first-page":"789","DOI":"10.1002\/art.41600","article-title":"RNA Sequencing Reveals Interacting Key Determinants of Osteoarthritis Acting in Subchondral Bone and Articular Cartilage: Identification of IL11 and CHADL as Attractive Treatment Targets","volume":"73","author":"Tuerlings","year":"2021","journal-title":"Arthritis Rheumatol."},{"key":"B70","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1016\/j.jot.2020.12.005","article-title":"SLCO2A1 Gene Is the Causal Gene for Both Primary Hypertrophic Osteoarthropathy and Hereditary Chronic Enteropathy","volume":"28","author":"Umeno","year":"2021","journal-title":"J. Orthop. Translat."},{"key":"B71","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1038\/nrrheum.2010.191","article-title":"Genetic Epidemiology of Hip and Knee Osteoarthritis","volume":"7","author":"Valdes","year":"2011","journal-title":"Nat. Rev. Rheumatol."},{"key":"B72","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1038\/nrrheum.2016.219","article-title":"The Changing Role of TGF\u03b2 in Healthy, Ageing and Osteoarthritic Joints","volume":"13","author":"van der Kraan","year":"2017","journal-title":"Nat. Rev. Rheumatol."},{"key":"B73","doi-asserted-by":"publisher","first-page":"569","DOI":"10.1136\/annrheumdis-2014-205743","article-title":"PPAR\u03b3 Deficiency Results in Severe, Accelerated Osteoarthritis Associated With Aberrant mTOR Signalling in the Articular Cartilage","volume":"74","author":"Vasheghani","year":"2015","journal-title":"Ann. Rheum. Dis."},{"key":"B74","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1016\/B978-0-12-405943-6.00008-7","article-title":"Hey BHLH Transcription Factors","volume":"110","author":"Weber","year":"2014","journal-title":"Curr. Top. Dev. Biol."},{"key":"B75","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1007\/s00418-002-0443-x","article-title":"Involvement of Sensory Nerves and Immune Cells in Osteophyte Formation in the Ankle Joint of Adjuvant Arthritic Rats","volume":"118","author":"Wu","year":"2002","journal-title":"Histochem. Cel Biol."},{"key":"B76","doi-asserted-by":"publisher","first-page":"1575","DOI":"10.1016\/j.joca.2015.04.016","article-title":"NOD2 Pathway via RIPK2 and TBK1 Is Involved in the Aberrant Catabolism Induced by T-2 Toxin in Chondrocytes","volume":"23","author":"Xu","year":"2015","journal-title":"Osteoarthritis Cartilage."},{"key":"B77","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1080\/15548627.2019.1606647","article-title":"MTORC1 Coordinates the Autophagy and Apoptosis Signaling in Articular Chondrocytes in Osteoarthritic Temporomandibular Joint","volume":"16","author":"Yang","year":"2020","journal-title":"Autophagy."},{"key":"B78","doi-asserted-by":"publisher","first-page":"687","DOI":"10.1038\/nm.2153","article-title":"Hypoxia-Inducible Factor-2Alpha Is a Catabolic Regulator of Osteoarthritic Cartilage Destruction","volume":"16","author":"Yang","year":"2010","journal-title":"Nat. Med."},{"key":"B79","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1136\/annrheumdis-2013-204355","article-title":"NAMPT (Visfatin), a Direct Target of Hypoxia-Inducible Factor-2\u03b1, Is an Essential Catabolic Regulator of Osteoarthritis","volume":"74","author":"Yang","year":"2015","journal-title":"Ann. Rheum. Dis."},{"key":"B80","doi-asserted-by":"publisher","first-page":"748","DOI":"10.1136\/annrheumdis-2012-201745","article-title":"A Novel Disease-Modifying Osteoarthritis Drug Candidate Targeting Runx1","volume":"72","author":"Yano","year":"2013","journal-title":"Ann. Rheum. Dis."},{"key":"B81","doi-asserted-by":"publisher","first-page":"7666","DOI":"10.1038\/s41598-019-43948-3","article-title":"Runx1 Contributes to Articular Cartilage Maintenance by Enhancement of Cartilage Matrix Production and Suppression of Hypertrophic Differentiation","volume":"9","author":"Yano","year":"2019","journal-title":"Sci. Rep."},{"key":"B82","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1038\/s41413-020-00109-x","article-title":"Classification of Four Distinct Osteoarthritis Subtypes With a Knee Joint Tissue Transcriptome Atlas","volume":"8","author":"Yuan","year":"2020","journal-title":"Bone Res."},{"key":"B83","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1016\/j.jbspin.2014.10.003","article-title":"Role of HIF-1\u03b1 and HIF-2\u03b1 in Osteoarthritis","volume":"82","author":"Zhang","year":"2015","journal-title":"Jt. Bone Spine."},{"key":"B84","doi-asserted-by":"publisher","first-page":"704","DOI":"10.1038\/nm.3143","article-title":"Inhibition of TGF-\u03b2 Signaling in Mesenchymal Stem Cells of Subchondral Bone Attenuates Osteoarthritis","volume":"19","author":"Zhen","year":"2013","journal-title":"Nat. Med."},{"key":"B85","doi-asserted-by":"publisher","first-page":"1523","DOI":"10.1038\/s41467-019-09234-6","article-title":"Metascape Provides a Biologist-Oriented Resource for the Analysis of Systems-Level Datasets","volume":"10","author":"Zhou","year":"2019","journal-title":"Nat. Commun."},{"key":"B86","doi-asserted-by":"publisher","first-page":"1420","DOI":"10.1136\/annrheumdis-2018-214940","article-title":"PPAR\u03b3 Preservation via Promoter Demethylation Alleviates Osteoarthritis in Mice","volume":"78","author":"Zhu","year":"2019","journal-title":"Ann. Rheum. Dis."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2021.730587\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,8,23]],"date-time":"2021-08-23T06:43:31Z","timestamp":1629701011000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2021.730587\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,23]]},"references-count":86,"alternative-id":["10.3389\/fphar.2021.730587"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2021.730587","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,23]]},"article-number":"730587"}}