{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T02:07:58Z","timestamp":1780625278346,"version":"3.54.1"},"reference-count":34,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,6,9]],"date-time":"2022-06-09T00:00:00Z","timestamp":1654732800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:p>Bacterial infection within the synovial joint, commonly known as septic arthritis, remains a clinical challenge as it presents two concurrent therapeutic goals of reducing bacterial burden and preservation of articular cartilage from destructive host inflammation. We hypothesized that mitigation of MRSA-induced inflammatory signaling could diminish destruction of articular cartilage in the setting of septic arthritis when used in conjunction with antibiotics. Herein, we provide evidence which supports a new therapeutic notion that concurrent antimicrobial therapy to address the \u2018septic\u2019 component of the disease with inflammation mitigation to manage the destructive \u2018arthritis\u2019 component. We established a murine model to mimic septic knee arthritis, as well as a variety of other inflammatory joint conditions. This murine septic arthritis model, in conjunction with <jats:italic>in vitro<\/jats:italic> and ex-vivo models, was utilized to characterize the inflammatory profile seen in active septic arthritis, as well as post-antibiotic treatment, <jats:italic>via<\/jats:italic> transcriptomic and histologic studies. Finally, we provided the clinical rationale for a novel therapeutic strategy combining enhanced antibiotic treatment with rifampin and adjuvant immunomodulation to inhibit post-infectious, excess chondrolysis and osteolysis. We identified that septic arthritis secondary to MRSA infection in our murine model led to increased articular cartilage damage compared to various types of inflammatory arthritis. The activation of the pERK1\/2 signaling pathway, which is implicated with the mounting of an immune response and generation of inflammation, was increased in intracellular MRSA-infected synovial tissue and persisted despite antibiotic treatment. Trametinib, an inhibitor of ERK signaling through suppression of MEK1\/2, alleviated the inflammation produced by the addition of intra-articular, heat-killed MRSA. Further, when combined with vancomycin and rifampin, mitigation of inflammation by pERK1\/2 targeting improved outcomes for MRSA septic arthritis by conferring chondroprotection to articular cartilage and diminishing inflammatory osteolysis within bone. Our results support a new therapeutic notion that cell\/biofilm-penetrating antibiotics alongside adjuvant mitigation of excessive intra-articular inflammation accomplish distinct therapeutic goals: reduction of bacterial burden and preservation of articular cartilage integrity.<\/jats:p>","DOI":"10.3389\/fcimb.2022.897291","type":"journal-article","created":{"date-parts":[[2022,6,9]],"date-time":"2022-06-09T04:53:26Z","timestamp":1654750406000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":13,"title":["Treating \u2018Septic\u2019 With Enhanced Antibiotics and \u2018Arthritis\u2019 by Mitigation of Excessive Inflammation"],"prefix":"10.3389","volume":"12","author":[{"given":"Hyuk-Kwon","family":"Kwon","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher M.","family":"Dussik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sang-Hun","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Themis R.","family":"Kyriakides","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irvin","family":"Oh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francis Y.","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,6,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"115568","DOI":"10.1016\/j.bone.2020.115568","article-title":"Intracellular Staphylococcus Aureus in Bone and Joint Infections: A Mechanism of Disease Recurrence, Inflammation, and Bone and Cartilage Destruction","volume":"141","author":"Alder","year":"2020","journal-title":"Bone"},{"key":"B2","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1038\/s41413-021-00158-w","article-title":"Inflammatory Conversion of Quiescent Osteoblasts by Metastatic Breast Cancer Cells Through pERK1\/2 Aggravates Cancer-Induced Bone Destruction","volume":"9","author":"Back","year":"2021","journal-title":"Bone Res."},{"key":"B3","first-page":"2474","article-title":"Management of Staphylococcus Aureus Infections","volume":"72","author":"Bamberger","year":"2005","journal-title":"Am. Fam. Physician"},{"key":"B4","doi-asserted-by":"publisher","first-page":"16878","DOI":"10.1038\/s41598-017-17204-5","article-title":"Qupath: Open Source Software for Digital Pathology Image Analysis","volume":"7","author":"Bankhead","year":"2017","journal-title":"Sci. Rep."},{"key":"B5","doi-asserted-by":"publisher","first-page":"402","DOI":"10.1002\/jor.24965","article-title":"Locally Delivered Adjuvant Biofilm-Penetrating Antibiotics Rescue Impaired Endochondral Fracture Healing Caused by MRSA Infection","volume":"39","author":"Cahill","year":"2021","journal-title":"J. Orthop. Res."},{"key":"B6","doi-asserted-by":"publisher","first-page":"781","DOI":"10.1111\/j.1553-2712.2011.01121.x","article-title":"Evidence-Based Diagnostics: Adult Septic Arthritis","volume":"18","author":"Carpenter","year":"2011","journal-title":"Acad. Emerg. Med."},{"key":"B7","doi-asserted-by":"publisher","first-page":"731","DOI":"10.1016\/S0140-6736(06)68231-7","article-title":"Complete Genome Sequence of USA300, an Epidemic Clone of Community-Acquired Meticillin-Resistant Staphylococcus Aureus","volume":"367","author":"Diep","year":"2006","journal-title":"Lancet"},{"key":"B8","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1136\/ard.61.3.267","article-title":"No Changes in the Distribution of Organisms Responsible for Septic Arthritis Over a 20 Year Period","volume":"61","author":"Dubost","year":"2002","journal-title":"Ann. Rheum. Dis."},{"key":"B9","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1038\/s41577-019-0215-7","article-title":"DAMP-Sensing Receptors in Sterile Inflammation and Inflammatory Diseases","volume":"20","author":"Gong","year":"2020","journal-title":"Nat. Rev. Immunol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"R1140","DOI":"10.1186\/ar1797","article-title":"Tumour Necrosis Factor Activates the Mitogen-Activated Protein Kinases p38alpha and ERK in the Synovial Membrane In Vivo","volume":"7","author":"Gortz","year":"2005","journal-title":"Arthritis Res. Ther."},{"key":"B11","doi-asserted-by":"publisher","first-page":"932","DOI":"10.1001\/jama.1976.03270090026021","article-title":"Residual Effects of Septic Arthritis in Infancy and Childhood","volume":"236","author":"Howard","year":"1976","journal-title":"JAMA"},{"key":"B12","doi-asserted-by":"publisher","first-page":"884","DOI":"10.1002\/art.1780400516","article-title":"The Outcome of Bacterial Arthritis: A Prospective Community-Based Study","volume":"40","author":"Kaandorp","year":"1997","journal-title":"Arthritis Rheum."},{"key":"B13","doi-asserted-by":"publisher","first-page":"509","DOI":"10.1038\/s41586-020-2760-4","article-title":"Structural Basis for the Action of the Drug Trametinib at KSR-bound Mek","volume":"588","author":"Khan","year":"2020","journal-title":"Nature"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abf2665","article-title":"Dual Therapeutic Targeting of Intra-Articular Inflammation and Intracellular Bacteria Enhances Chondroprotection in Septic Arthritis","volume":"7","author":"Kwon","year":"2021","journal-title":"Sci. Adv."},{"key":"B15","doi-asserted-by":"publisher","first-page":"9197","DOI":"10.1016\/j.biomaterials.2011.08.059","article-title":"Actin and ERK1\/2-CEBPbeta Signaling Mediates Phagocytosis-Induced Innate Immune Response of Osteoprogenitor Cells","volume":"32","author":"Lee","year":"2011","journal-title":"Biomaterials"},{"key":"B16","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1056\/NEJMoa1710926","article-title":"Oral Versus Intravenous Antibiotics for Bone and Joint Infection","volume":"380","author":"Li","year":"2019","journal-title":"N Engl. J. Med."},{"key":"B17","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1093\/cid\/cir034","article-title":"Clinical Practice Guidelines by the Infectious Diseases Society of America for the Treatment of Methicillin-Resistant Staphylococcus Aureus Infections in Adults and Children: Executive Summary","volume":"52","author":"Liu","year":"2011","journal-title":"Clin. Infect. Dis."},{"key":"B18","doi-asserted-by":"publisher","first-page":"846","DOI":"10.1016\/S0140-6736(09)61595-6","article-title":"Bacterial Septic Arthritis in Adults","volume":"375","author":"Mathews","year":"2010","journal-title":"Lancet"},{"key":"B19","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1038\/nrmicro2539","article-title":"Modulation of NF-kappaB Signalling by Microbial Pathogens","volume":"9","author":"Rahman","year":"2011","journal-title":"Nat. Rev. Microbiol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"835","DOI":"10.1093\/ajhp\/zxaa036","article-title":"Therapeutic Monitoring of Vancomycin for Serious Methicillin-Resistant Staphylococcus Aureus Infections: A Revised Consensus Guideline and Review by the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists","volume":"77","author":"Rybak","year":"2020","journal-title":"Am. J. Health Syst. Pharm."},{"key":"B21","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1097\/BLO.0b013e3181123d4e","article-title":"Higher Risk of Failure of Methicillin-Resistant Staphylococcus Aureus Prosthetic Joint Infections","volume":"461","author":"Salgado","year":"2007","journal-title":"Clin. Orthop. Relat. Res."},{"key":"B22","doi-asserted-by":"publisher","first-page":"2501","DOI":"10.1002\/1529-0131(200011)43:11<2501::AID-ANR18>3.0.CO;2-K","article-title":"Activation, Differential Localization, and Regulation of the Stress-Activated Protein Kinases, Extracellular Signal-Regulated Kinase, C-JUN N-terminal Kinase, and p38 Mitogen-Activated Protein Kinase, in Synovial Tissue and Cells in Rheumatoid Arthritis","volume":"43","author":"Schett","year":"2000","journal-title":"Arthritis Rheum."},{"key":"B23","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1038\/nmeth.2089","article-title":"Nih Image to ImageJ: 25 Years of Image Analysis","volume":"9","author":"Schneider","year":"2012","journal-title":"Nat. Methods"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2017.00152","article-title":"Laboratory Mice Are Frequently Colonized With Staphylococcus Aureus and Mount a Systemic Immune Response-Note of Caution for In Vivo Infection Experiments","volume":"7","author":"Schulz","year":"2017","journal-title":"Front. Cell Infect. Microbiol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"695","DOI":"10.1016\/j.bone.2009.10.032","article-title":"Targeting Extracellular Signal-Regulated Kinase (ERK) Signaling has Therapeutic Implications for Inflammatory Osteolysis","volume":"46","author":"Seo","year":"2010","journal-title":"Bone"},{"key":"B26","doi-asserted-by":"publisher","first-page":"8258","DOI":"10.4049\/jimmunol.0901784","article-title":"ERK-Dependent T Cell Receptor Threshold Calibration in Rheumatoid Arthritis","volume":"183","author":"Singh","year":"2009","journal-title":"J. Immunol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1093\/rheumatology\/kem297","article-title":"Mapks and Their Relevance to Arthritis and Inflammation","volume":"47","author":"Thalhamer","year":"2008","journal-title":"Rheumatol. (Oxford)"},{"key":"B28","doi-asserted-by":"publisher","first-page":"3347","DOI":"10.1002\/art.22869","article-title":"Central Role of the MEK\/ERK MAP Kinase Pathway in a Mouse Model of Rheumatoid Arthritis: Potential Proinflammatory Mechanisms","volume":"56","author":"Thiel","year":"2007","journal-title":"Arthritis Rheum."},{"key":"B29","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1097\/00003086-199002000-00040","article-title":"Septic Arthritis in the Elderly","author":"Vincent","year":"1990","journal-title":"Clin. Orthop. Relat. Res."},{"key":"B30","first-page":"41","article-title":"Septic Arthritis in Children: Relationship of Causative Pathogens, Complications, and Outcome","volume":"36","author":"Wang","year":"2003","journal-title":"J. Microbiol. Immunol. Infect."},{"key":"B31","doi-asserted-by":"publisher","first-page":"669","DOI":"10.1097\/00006454-198611000-00014","article-title":"Pyogenic Arthritis in Infants and Children: A Review of 95 Cases","volume":"5","author":"Welkon","year":"1986","journal-title":"Pediatr. Infect. Dis."},{"key":"B32","doi-asserted-by":"publisher","first-page":"214","DOI":"10.1136\/ard.58.4.214","article-title":"Clinical Features and Outcome of Septic Arthritis in a Single UK Health District 1982-1991","volume":"58","author":"Weston","year":"1999","journal-title":"Ann. Rheum. Dis."},{"key":"B33","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1302\/2046-3758.92.BJR-2019-0131.R1","article-title":"Recalcitrant Methicillin-Resistant Staphylococcus Aureus Infection of Bone Cells: Intracellular Penetration and Control Strategies","volume":"9","author":"Yu","year":"2020","journal-title":"Bone Joint Res."},{"key":"B34","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1146\/annurev-pathmechdis-012419-032847","article-title":"Damps, PAMPs, and LAMPs in Immunity and Sterile Inflammation","volume":"15","author":"Zindel","year":"2020","journal-title":"Annu. Rev. Pathol."}],"container-title":["Frontiers in Cellular and Infection Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2022.897291\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,6,9]],"date-time":"2022-06-09T04:53:30Z","timestamp":1654750410000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2022.897291\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,9]]},"references-count":34,"alternative-id":["10.3389\/fcimb.2022.897291"],"URL":"https:\/\/doi.org\/10.3389\/fcimb.2022.897291","relation":{},"ISSN":["2235-2988"],"issn-type":[{"value":"2235-2988","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,9]]},"article-number":"897291"}}