{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T19:03:01Z","timestamp":1793041381143,"version":"4.5.0"},"reference-count":49,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2021,2,25]],"date-time":"2021-02-25T00:00:00Z","timestamp":1614211200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Osteoarthritis (OA) is one of the most common and widespread diseases which is highly disabling for humans. This makes OA a chronic disease for which it is urgent to find new therapeutic strategies. The inflammatory state in OA contributes to its progression through multiple mechanisms involving the recruitment of phagocytes and leukocytes, inflammatory response, and reactive oxygen species (ROS) production. Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl) is classifiable as a piperidine nitroxide, with excellent antioxidant effects, while its anti-inflammatory role is not yet clear. On this basis, we explored its promising biological properties in two in vitro model:, macrophage (J774) and chondrocyte (CC) cell lines. With this aim in mind, we induced inflammation in J774 and CC using lipopolysaccharide (LPS) and Interleukin1\u03b2 (IL-1\u03b2), and after 24, 72 and 168 h of tempol treatment analyzed their effects on cytotoxicity and anti-inflammatory activity. Our data suggested that tempol treatment is able to reduce inflammation and nitrite production in LPS-induced J774 as well as reducing the production of proinflammatory mediators including cytokines, enzymes, and metalloproteases (MMPs) in IL-1\u03b2-stimulated CC. Thus, since inflammation and oxidative stress have a crucial role in the pathogenesis and progression of OA, tempol could be considered as a new therapeutic approach for this pathology.<\/jats:p>","DOI":"10.3390\/biom11030352","type":"journal-article","created":{"date-parts":[[2021,2,25]],"date-time":"2021-02-25T21:16:53Z","timestamp":1614287813000},"page":"352","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Beneficial Effect of Tempol, a Membrane-Permeable Radical Scavenger, on Inflammation and Osteoarthritis in In Vitro Models"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1937-5403","authenticated-orcid":false,"given":"Giovanna","family":"Calabrese","sequence":"first","affiliation":[{"name":"Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D\u05f3Alcontres, 31-98166 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2293-0634","authenticated-orcid":false,"given":"Alessio","family":"Ardizzone","sequence":"additional","affiliation":[{"name":"Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D\u05f3Alcontres, 31-98166 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michela","family":"Campolo","sequence":"additional","affiliation":[{"name":"Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D\u05f3Alcontres, 31-98166 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina","family":"Conoci","sequence":"additional","affiliation":[{"name":"Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D\u05f3Alcontres, 31-98166 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2663-6387","authenticated-orcid":false,"given":"Emanuela","family":"Esposito","sequence":"additional","affiliation":[{"name":"Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D\u05f3Alcontres, 31-98166 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Paterniti","sequence":"additional","affiliation":[{"name":"Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D\u05f3Alcontres, 31-98166 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,2,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"99","DOI":"10.20344\/amp.5477","article-title":"Osteoarthritis","volume":"28","author":"Pereira","year":"2015","journal-title":"Acta Med. Port."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/j.joca.2020.01.002","article-title":"Osteoarthritis year in review 2019: Epidemiology and therapy","volume":"28","author":"Kloppenburg","year":"2020","journal-title":"Osteoarthr. Cartil."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1016\/j.pop.2013.08.003","article-title":"Diagnosis and treatment of osteoarthritis","volume":"40","author":"Lynch","year":"2013","journal-title":"Prim. Care"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/0021-9290(84)90031-9","article-title":"Fluid transport and mechanical properties of articular cartilage: A review","volume":"17","author":"Mow","year":"1984","journal-title":"J. Biomech."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1016\/S0140-6736(14)60802-3","article-title":"Osteoarthritis","volume":"386","author":"Palmer","year":"2015","journal-title":"Lancet"},{"key":"ref_6","first-page":"173","article-title":"Non-Pharmacological and Non-Surgical Interventions for Knee Osteoarthritis: A Systematic Review and Meta-Analysis","volume":"44","author":"Ferreira","year":"2019","journal-title":"Acta Reumatol. Port."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"117","DOI":"10.2174\/1573397113666170810151638","article-title":"Potentials and Limits of Physiotherapy in Osteoarthritis","volume":"14","author":"Richter","year":"2018","journal-title":"Curr. Rheumatol. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Rutjes, A.W., Nuesch, E., Sterchi, R., Kalichman, L., Hendriks, E., Osiri, M., Brosseau, L., Reichenbach, S., and Juni, P. (2009). Transcutaneous electrostimulation for osteoarthritis of the knee. Cochrane Database Syst. Rev.","DOI":"10.1002\/14651858.CD002823.pub2"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1080\/03008207.2016.1208655","article-title":"Inflammation and epigenetic regulation in osteoarthritis","volume":"58","author":"Shen","year":"2017","journal-title":"Connect. Tissue Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.freeradbiomed.2018.08.038","article-title":"Reactive oxygen species, aging and articular cartilage homeostasis","volume":"132","author":"Bolduc","year":"2019","journal-title":"Free Radic. Biol. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1016\/j.bbadis.2016.01.003","article-title":"ROS\/oxidative stress signaling in osteoarthritis","volume":"1862","author":"Lepetsos","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1007\/s00296-006-0247-8","article-title":"Increased oxidative stress and its relation with collagen metabolism in knee osteoarthritis","volume":"27","author":"Altindag","year":"2007","journal-title":"Rheumatol. Int."},{"key":"ref_13","first-page":"44","article-title":"The Role of Aging in the Development of Osteoarthritis","volume":"128","author":"Loeser","year":"2017","journal-title":"Trans. Am. Clin. Climatol. Assoc."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1087","DOI":"10.1016\/j.joca.2017.07.020","article-title":"Parkin clearance of dysfunctional mitochondria regulates ROS levels and increases survival of human chondrocytes","volume":"26","author":"Ansari","year":"2018","journal-title":"Osteoarthr. Cartil."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1038\/nrrheum.2016.65","article-title":"Ageing and the pathogenesis of osteoarthritis","volume":"12","author":"Loeser","year":"2016","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1016\/j.jbspin.2007.02.002","article-title":"Reactive oxygen species and superoxide dismutases: Role in joint diseases","volume":"74","author":"Afonso","year":"2007","journal-title":"Joint Bone Spine"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3419","DOI":"10.1002\/art.11338","article-title":"Increased oxidative stress with aging reduces chondrocyte survival: Correlation with intracellular glutathione levels","volume":"48","author":"Carlo","year":"2003","journal-title":"Arthritis Rheum."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"6641","DOI":"10.1074\/jbc.M115.693523","article-title":"Oxidative Stress Promotes Peroxiredoxin Hyperoxidation and Attenuates Pro-survival Signaling in Aging Chondrocytes","volume":"291","author":"Collins","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1452","DOI":"10.1021\/acschemneuro.6b00211","article-title":"Novel Synthetic PEGylated Conjugate of alpha-Lipoic Acid and Tempol Reduces Cell Death in a Neuronal PC12 Clonal Line Subjected to Ischemia","volume":"7","author":"Lahiani","year":"2016","journal-title":"ACS Chem. Neurosci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/j.freeradbiomed.2020.06.013","article-title":"Improvement in cardiac function of ovariectomized rats by antioxidant tempol","volume":"160","author":"Phungphong","year":"2020","journal-title":"Free Radic. Biol. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"109210","DOI":"10.1016\/j.cbi.2020.109210","article-title":"Tempol reduces inflammation and oxidative damage in cigarette smoke-exposed mice by decreasing neutrophil infiltration and activating the Nrf2 pathway","volume":"329","author":"Silva","year":"2020","journal-title":"Chem. Biol. Interact."},{"key":"ref_22","first-page":"4847","article-title":"Piperidine nitroxide Tempol enhances cisplatin-induced apoptosis in ovarian cancer cells","volume":"16","author":"Wang","year":"2018","journal-title":"Oncol. Lett."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1124\/pr.108.000240","article-title":"Chemistry and antihypertensive effects of tempol and other nitroxides","volume":"60","author":"Wilcox","year":"2008","journal-title":"Pharmacol. Rev."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1097\/HJH.0000000000000422","article-title":"Efficacy of the superoxide dismutase mimetic tempol in animal hypertension models: A meta-analysis","volume":"33","author":"Dornas","year":"2015","journal-title":"J. Hypertens."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Jia, D., Wang, H., Han, B., Zhang, L., and Guo, J. (2019). Tempol Attenuates Neuropathic Pain by Inhibiting Nitric Oxide Production. Anal Cell Pathol., 2019.","DOI":"10.1155\/2019\/8253850"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/S0014-2999(00)00623-3","article-title":"Tempol, a membrane-permeable radical scavenger, reduces dinitrobenzene sulfonic acid-induced colitis","volume":"406","author":"Cuzzocrea","year":"2000","journal-title":"Eur. J. Pharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"9571","DOI":"10.2147\/OTT.S221733","article-title":"miR-19a Is Involved In Progression And Malignancy Of Anaplastic Thyroid Cancer Cells","volume":"12","author":"Calabrese","year":"2019","journal-title":"OncoTargets Ther."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Adesso, S., Paterniti, I., Cuzzocrea, S., Fujioka, M., Autore, G., Magnus, T., Pinto, A., and Marzocco, S. (2018). AST-120 Reduces Neuroinflammation Induced by Indoxyl Sulfate in Glial Cells. J. Clin. Med., 7.","DOI":"10.3390\/jcm7100365"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1016\/j.stemcr.2019.10.005","article-title":"Closing the Mitochondrial Permeability Transition Pore in hiPSC-Derived Endothelial Cells Induces Glycocalyx Formation and Functional Maturation","volume":"13","author":"Tiemeier","year":"2019","journal-title":"Stem Cell Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.taap.2014.03.026","article-title":"Attenuation of Abeta25-35-induced parallel autophagic and apoptotic cell death by gypenoside XVII through the estrogen receptor-dependent activation of Nrf2\/ARE pathways","volume":"279","author":"Meng","year":"2014","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Vicari, L., Calabrese, G., Forte, S., Giuffrida, R., Colarossi, C., Parrinello, N.L., and Memeo, L. (2016). Potential Role of Activating Transcription Factor 5 during Osteogenesis. Stem Cells Int., 2016.","DOI":"10.1155\/2016\/5282185"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"98","DOI":"10.2174\/1573397113666170807122312","article-title":"Novel Insights into the Pathogenesis of Osteoarthritis","volume":"14","author":"Geyer","year":"2018","journal-title":"Curr. Rheumatol. Rev."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1038\/s41584-019-0221-y","article-title":"Therapeutic options for targeting inflammatory osteoarthritis pain","volume":"15","author":"Conaghan","year":"2019","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1038\/nrrheum.2014.162","article-title":"Emerging regulators of the inflammatory process in osteoarthritis","volume":"11","author":"Terkeltaub","year":"2015","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1097\/BOR.0000000000000353","article-title":"Role of low-grade inflammation in osteoarthritis","volume":"29","author":"Scanzello","year":"2017","journal-title":"Curr. Opin. Rheumatol."},{"key":"ref_36","first-page":"57","article-title":"Innate inflammation and synovial macrophages in osteoarthritis pathophysiology","volume":"37 Suppl 120","author":"Griffin","year":"2019","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1038\/nrrheum.2016.136","article-title":"Low-grade inflammation as a key mediator of the pathogenesis of osteoarthritis","volume":"12","author":"Robinson","year":"2016","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"41988","DOI":"10.18632\/oncotarget.16716","article-title":"Pterostilbene inhibits inflammation and ROS production in chondrocytes by activating Nrf2 pathway","volume":"8","author":"Xue","year":"2017","journal-title":"Oncotarget"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.lfs.2019.02.016","article-title":"Tempol improves oxidant\/antioxidant parameters in testicular tissues of diabetic rats","volume":"221","author":"Shateri","year":"2019","journal-title":"Life Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.3349\/ymj.2018.59.9.1079","article-title":"Effects of Antioxidant Tempol on Systematic Inflammation and Endothelial Apoptosis in Emphysematous Rats Exposed to Intermittent Hypoxia","volume":"59","author":"Zhao","year":"2018","journal-title":"Yonsei Med. J."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1177\/0960327119836203","article-title":"Anti-inflammatory role of tempol (4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl) in nephroprotection","volume":"38","author":"Afjal","year":"2019","journal-title":"Hum Exp Toxicol"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.tvjl.2015.07.011","article-title":"In vitro models for the study of osteoarthritis","volume":"209","author":"Johnson","year":"2016","journal-title":"Vet. J."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.cytogfr.2019.03.004","article-title":"Clinical implications of macrophage dysfunction in the development of osteoarthritis of the knee","volume":"46","author":"Xie","year":"2019","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Cai, S., Ming, B., Ye, C., Lin, S., Hu, P., Tang, J., Zheng, F., and Dong, L. (2019). Similar Transition Processes in Synovial Fibroblasts from Rheumatoid Arthritis and Osteoarthritis: A Single-Cell Study. J. Immunol. Res., 2019.","DOI":"10.1155\/2019\/4080735"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1097\/BOR.0b013e328349c2b1","article-title":"Inflammation in osteoarthritis","volume":"23","author":"Goldring","year":"2011","journal-title":"Curr. Opin. Rheumatol."},{"key":"ref_46","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_47","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.cytogfr.2018.10.002","article-title":"Pro-inflammatory cytokines: The link between obesity and osteoarthritis","volume":"44","author":"Wang","year":"2018","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"14811","DOI":"10.4238\/2015.November.18.46","article-title":"High MMP-1, MMP-2, and MMP-9 protein levels in osteoarthritis","volume":"14","author":"Zeng","year":"2015","journal-title":"Genet. Mol. Res."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Rose, B.J., and Kooyman, D.L. (2016). A Tale of Two Joints: The Role of Matrix Metalloproteases in Cartilage Biology. Dis. Markers, 2016.","DOI":"10.1155\/2016\/4895050"}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/11\/3\/352\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:28:49Z","timestamp":1760160529000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/11\/3\/352"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,25]]},"references-count":49,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2021,3]]}},"alternative-id":["biom11030352"],"URL":"https:\/\/doi.org\/10.3390\/biom11030352","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,25]]}}}