{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T11:20:46Z","timestamp":1788348046876,"version":"build-2803163510"},"reference-count":54,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2018,5,9]],"date-time":"2018-05-09T00:00:00Z","timestamp":1525824000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education","award":["2013R1A1A2058776"],"award-info":[{"award-number":["2013R1A1A2058776"]}]},{"name":"Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education","award":["2015R1D1A1A01058168"],"award-info":[{"award-number":["2015R1D1A1A01058168"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Osteoarthritis (OA) is the most common and increasing joint disease worldwide. Current treatment for OA is limited to control of symptoms. The purpose of this study was to determine the effect of specificity protein 1 (SP1) inhibitor Mithramycin A (MitA) on chondrocyte catabolism and OA pathogenesis and to explore the underlying molecular mechanisms involving SP1 and other key factors that are critical for OA. Here, we show that MitA markedly inhibited expressions of matrix-degrading enzymes induced by pro-inflammatory cytokine interleukin-1\u03b2 (IL-1\u03b2) in mouse primary chondrocytes. Intra-articular injection of MitA into mouse knee joint alleviated OA cartilage destruction induced by surgical destabilization of the medial meniscus (DMM). However, modulation of SP1 level in chondrocyte and mouse cartilage did not alter catabolic gene expression or cartilage integrity, respectively. Instead, MitA significantly impaired the expression of HIF-2\u03b1 known to be critical for OA pathogenesis. Such reduction in expression of HIF-2\u03b1 by MitA was caused by inhibition of NF-\u03baB activation, at least in part. These results suggest that MitA can alleviate OA pathogenesis by suppressing NF-\u03baB-HIF-2\u03b1 pathway, thus providing insight into therapeutic strategy for OA.<\/jats:p>","DOI":"10.3390\/ijms19051411","type":"journal-article","created":{"date-parts":[[2018,5,10]],"date-time":"2018-05-10T03:48:27Z","timestamp":1525924107000},"page":"1411","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Mithramycin A Alleviates Osteoarthritic Cartilage Destruction by Inhibiting HIF-2\u03b1 Expression"],"prefix":"10.3390","volume":"19","author":[{"given":"Moon-Chang","family":"Choi","sequence":"first","affiliation":[{"name":"School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 61005, Korea"},{"name":"Department of Biomedical Science, Chosun University, Gwangju 61452, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Woo Hee","family":"Choi","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 61005, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,5,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1002\/jcp.21258","article-title":"Osteoarthritis","volume":"213","author":"Goldring","year":"2007","journal-title":"J. Cell. Physiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"15040","DOI":"10.1038\/boneres.2015.40","article-title":"Current research on pharmacologic and regenerative therapies for osteoarthritis","volume":"4","author":"Zhang","year":"2016","journal-title":"Bone Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"74","DOI":"10.2741\/e361","article-title":"Osteoarthritis: Genetic factors, animal models, mechanisms, and therapies","volume":"4","author":"Bian","year":"2012","journal-title":"Front. Biosci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1038\/nrrheum.2012.130","article-title":"Bone remodelling in osteoarthritis","volume":"8","author":"Burr","year":"2012","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1038\/nrrheum.2010.198","article-title":"The role of the cartilage matrix in osteoarthritis","volume":"7","author":"Heinegard","year":"2011","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1038\/nrm3904","article-title":"Remodelling the extracellular matrix in development and disease","volume":"15","author":"Bonnans","year":"2014","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1002\/art.22337","article-title":"Crucial role of macrophages in matrix metalloproteinase-mediated cartilage destruction during experimental osteoarthritis: Involvement of matrix metalloproteinase 3","volume":"56","author":"Blom","year":"2007","journal-title":"Arthritis Rheum"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1038\/nature03369","article-title":"Deletion of active adamts5 prevents cartilage degradation in a murine model of osteoarthritis","volume":"434","author":"Glasson","year":"2005","journal-title":"Nature"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3723","DOI":"10.1002\/art.25002","article-title":"Matrix metalloproteinase 13-deficient mice are resistant to osteoarthritic cartilage erosion but not chondrocyte hypertrophy or osteophyte development","volume":"60","author":"Little","year":"2009","journal-title":"Arthritis Rheumatol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1186\/ar112","article-title":"Fibroblast biology. Effector signals released by the synovial fibroblast in arthritis","volume":"2","author":"Ritchlin","year":"2000","journal-title":"Arthritis Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4664","DOI":"10.1096\/fj.13-234542","article-title":"Fluid shear stress-induced osteoarthritis: Roles of cyclooxygenase-2 and its metabolic products in inducing the expression of proinflammatory cytokines and matrix metalloproteinases","volume":"27","author":"Wang","year":"2013","journal-title":"FASEB J."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/S1063-4584(97)80008-8","article-title":"Detection of interleukin-1 in the cartilage of patients with osteoarthritis: A possible autocrine\/paracrine role in pathogenesis","volume":"5","author":"Towle","year":"1997","journal-title":"Osteoarthr. Cartil."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1038\/nrrheum.2010.196","article-title":"Role of proinflammatory cytokines in the pathophysiology of osteoarthritis","volume":"7","author":"Kapoor","year":"2011","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_14","first-page":"237","article-title":"The role of cytokines in osteoarthritis pathophysiology","volume":"39","author":"Fernandes","year":"2002","journal-title":"Biorheology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1002\/art.1780380202","article-title":"Inhibition of the production and effects of interleukin-1 and tumor necrosis factor alpha in rheumatoid arthritis","volume":"38","author":"Arend","year":"1995","journal-title":"Arthritis Rheumatol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1038\/nm.2146","article-title":"Transcriptional regulation of endochondral ossification by hif-2alpha during skeletal growth and osteoarthritis development","volume":"16","author":"Saito","year":"2010","journal-title":"Nat. Med."},{"key":"ref_17","doi-asserted-by":"crossref","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":"ref_18","doi-asserted-by":"crossref","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":"ref_19","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/S0945-053X(02)00007-0","article-title":"Inhibition of interleukin-1-stimulated MAP kinases, activating protein-1 (AP-1) and nuclear factor kappa B (NF-kappa B) transcription factors down-regulates matrix metalloproteinase gene expression in articular chondrocytes","volume":"21","author":"Liacini","year":"2002","journal-title":"Matrix Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1002\/mpo.2950240511","article-title":"Long-term follow-up of stage iii testicular carcinoma treated with mithramycin (plicamycin)","volume":"24","author":"Kennedy","year":"1995","journal-title":"Med. Pediatr. Oncol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1056\/NEJM196501212720301","article-title":"Mithramycin in the treatment of disseminated testicular neoplasms","volume":"272","author":"Brown","year":"1965","journal-title":"N. Engl. J. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"8313","DOI":"10.1021\/bi034091z","article-title":"Inhibition of c-src transcription by mithramycin: Structure-activity relationships of biosynthetically produced mithramycin analogues using the c-src promoter as target","volume":"42","author":"Remsing","year":"2003","journal-title":"Biochemistry"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1006\/bbrc.1993.2178","article-title":"The majority of osteoclasts require mrna and protein synthesis for bone resorption in vitro","volume":"195","author":"Hall","year":"1993","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2003","DOI":"10.1172\/JCI114110","article-title":"Mithramycin blocks protein binding and function of the sv40 early promoter","volume":"83","author":"Ray","year":"1989","journal-title":"J. Clin. Investig."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s00253-006-0511-6","article-title":"The aureolic acid family of antitumor compounds: Structure, mode of action, biosynthesis, and novel derivatives","volume":"73","author":"Lombo","year":"2006","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"16672","DOI":"10.1074\/jbc.M511648200","article-title":"Sp1 is up-regulated in cellular and transgenic models of huntington disease, and its reduction is neuroprotective","volume":"281","author":"Qiu","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1111\/febs.13148","article-title":"Sp1 and the \u2018hallmarks of cancer\u2019","volume":"282","author":"Beishline","year":"2015","journal-title":"FEBS J."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"6858","DOI":"10.1523\/JNEUROSCI.0710-11.2011","article-title":"Mithramycin is a gene-selective sp1 inhibitor that identifies a biological intersection between cancer and neurodegeneration","volume":"31","author":"Sleiman","year":"2011","journal-title":"J. Neurosci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"7162","DOI":"10.1038\/srep07162","article-title":"Modulation of specificity protein 1 by mithramycin a as a novel therapeutic strategy for cervical cancer","volume":"4","author":"Choi","year":"2014","journal-title":"Sci. Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"19176","DOI":"10.1073\/pnas.0606373103","article-title":"Eset\/setdb1 gene expression and histone h3 (k9) trimethylation in huntington\u2019s disease","volume":"103","author":"Ryu","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"39967","DOI":"10.1074\/jbc.M112.397042","article-title":"Elevated SP-1 transcription factor expression and activity drives basal and hypoxia-induced vascular endothelial growth factor (VEGF) expression in non-small cell lung cancer","volume":"287","author":"Deacon","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1254\/jphs.13R02CP","article-title":"Mithramycin, an agent for developing new therapeutic drugs for neurodegenerative diseases","volume":"122","author":"Osada","year":"2013","journal-title":"J. Pharmacol. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"R777","DOI":"10.1186\/ar1735","article-title":"Mithramycin downregulates proinflammatory cytokine-induced matrix metalloproteinase gene expression in articular chondrocytes","volume":"7","author":"Liacini","year":"2005","journal-title":"Arthritis Res. Ther."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"202","DOI":"10.22203\/eCM.v021a16","article-title":"Roles of inflammatory and anabolic cytokines in cartilage metabolism: Signals and multiple effectors converge upon MMP-13 regulation in osteoarthritis","volume":"21","author":"Goldring","year":"2011","journal-title":"Eur. Cell Mater."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2580","DOI":"10.1016\/j.biocel.2013.08.018","article-title":"The NF-kappab signalling pathway in osteoarthritis","volume":"45","author":"Rigoglou","year":"2013","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1016\/j.joca.2006.04.008","article-title":"Nf-kappab as a potential therapeutic target in osteoarthritis and rheumatoid arthritis","volume":"14","author":"Jimenez","year":"2006","journal-title":"Osteoarthr. Cartil."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1139\/bcb-2017-0025","article-title":"Danshen attenuates osteoarthritis-related cartilage degeneration through inhibition of nf-kappab signaling pathway in vivo and in vitro","volume":"95","author":"Xu","year":"2017","journal-title":"Biochem. Cell Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3013","DOI":"10.3892\/etm.2017.4349","article-title":"Protective effect of shenmai injection on knee articular cartilage of osteoarthritic rabbits and IL-1beta-stimulated human chondrocytes","volume":"13","author":"Yao","year":"2017","journal-title":"Exp. Ther. Med."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Wang, K., Li, Y., Han, R., Cai, G., He, C., Wang, G., and Jia, D. (2017). T140 blocks the SDF-1\/CXCR4 signaling pathway and prevents cartilage degeneration in an osteoarthritis disease model. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0176048"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1007\/s00296-011-2187-1","article-title":"Role of sp1 transcription factor in interleukin-1-induced adamts-4 (aggrecanase-1) gene expression in human articular chondrocytes","volume":"33","author":"Sylvester","year":"2013","journal-title":"Rheumatol. Int."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"599","DOI":"10.2174\/138945010791011938","article-title":"NF-kappab signaling: Multiple angles to target OA","volume":"11","author":"Marcu","year":"2010","journal-title":"Curr. Drug Targets"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"6246","DOI":"10.4049\/jimmunol.179.9.6246","article-title":"Biomechanical signals suppress tak1 activation to inhibit nf-kappab transcriptional activation in fibrochondrocytes","volume":"179","author":"Madhavan","year":"2007","journal-title":"J. Immunol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"5781","DOI":"10.4049\/jimmunol.174.9.5781","article-title":"Nf-kappa b mediates the stimulation of cytokine and chemokine expression by human articular chondrocytes in response to fibronectin fragments","volume":"174","author":"Pulai","year":"2005","journal-title":"J. Immunol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1615\/CritRevEukarGeneExpr.v18.i2.30","article-title":"Regulation of chondrocytic gene expression by biomechanical signals","volume":"18","author":"Knobloch","year":"2008","journal-title":"Crit. Rev. Eukaryot. Gene Expr."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1158\/0008-5472.CAN-09-2327","article-title":"Apoptotic sensitivity of colon cancer cells to histone deacetylase inhibitors is mediated by an sp1\/sp3-activated transcriptional program involving immediate-early gene induction","volume":"70","author":"Wilson","year":"2010","journal-title":"Cancer Res."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Otjacques, E., Binsfeld, M., Rocks, N., Blacher, S., Vanderkerken, K., Noel, A., Beguin, Y., Cataldo, D., and Caers, J. (2013). Mithramycin exerts an anti-myeloma effect and displays anti-angiogenic effects through up-regulation of anti-angiogenic factors. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0062818"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1016\/j.fob.2014.10.007","article-title":"Anticancer drug mithramycin interacts with core histones: An additional mode of action of the DNA groove binder","volume":"4","author":"Banerjee","year":"2014","journal-title":"FEBS Open Bio"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Choi, M.C., MaruYama, T., Chun, C.H., and Park, Y. (2018). Alleviation of murine osteoarthritis by cartilage-specific deletion of ikappabzeta. Arthritis Rheumatol.","DOI":"10.1002\/art.40514"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.3390\/ph4081183","article-title":"Histone deacetylase inhibitors and mithramycin a impact a similar neuroprotective pathway at a crossroad between cancer and neurodegeneration","volume":"4","author":"Sleiman","year":"2011","journal-title":"Pharmaceuticals"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"7095","DOI":"10.1038\/sj.onc.1207932","article-title":"AKAP12\/Gravin is inactivated by epigenetic mechanism in human gastric carcinoma and shows growth suppressor activity","volume":"23","author":"Choi","year":"2004","journal-title":"Oncogene"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.15252\/embr.201439195","article-title":"HDAC4 promotes Pax7-dependent satellite cell activation and muscle regeneration","volume":"15","author":"Choi","year":"2014","journal-title":"EMBO Rep."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/j.molcel.2012.04.025","article-title":"A direct HDAC4-map kinase crosstalk activates muscle atrophy program","volume":"47","author":"Choi","year":"2012","journal-title":"Mol. Cell"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1083\/jcb.153.1.87","article-title":"Skeletal malformations caused by overexpression of CBFA1 or its dominant negative form in chondrocytes","volume":"153","author":"Ueta","year":"2001","journal-title":"J. Cell Biol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"S17","DOI":"10.1016\/j.joca.2010.05.025","article-title":"The OARSI histopathology initiative\u2014Recommendations for histological assessments of osteoarthritis in the mouse","volume":"18","author":"Glasson","year":"2010","journal-title":"Osteoarthr. Cartil."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/5\/1411\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:03:51Z","timestamp":1760195031000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/5\/1411"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,5,9]]},"references-count":54,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2018,5]]}},"alternative-id":["ijms19051411"],"URL":"https:\/\/doi.org\/10.3390\/ijms19051411","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,5,9]]}}}