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Lipid A composition was assessed using liquid chromatography\u2013mass spectrometry (LC-MS). In a rat model, LPS was administered systemically for 32 days to evaluate its impact on joint degeneration. The interaction between LPS and synovial proteins, particularly fibronectin (Fn), was examined through in vitro assays and a 3D synovial membrane model.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>LPS was detected in all SF samples with comparable concentrations and lipid A profiles across all groups. LC-MS measurements indicated higher LPS levels than those obtained from standard endotoxin assays, suggesting limitations in conventional detection methods. Despite elevated LPS presence, bioactivity assays revealed minimal proinflammatory responses, implying the existence of intrinsic SF factors neutralising LPS. In vivo, prolonged systemic LPS exposure did not induce OA-like changes in rat joints. Notably, LPS colocalised with Fn in the synovial membrane, and Fn binding attenuated LPS bioactivity and hindered its migration in vitro.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>LPS is prevalent in SF across various joint conditions but exhibits low bioactivity, indicating it is not a primary driver of joint inflammation. Fn plays a crucial role in sequestering and neutralising LPS within the synovial environment, offering a protective mechanism against LPS-induced inflammation. These findings underscore the need for accurate LPS measurement techniques and suggest potential therapeutic targets for modulating joint inflammation.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/rmdopen-2025-005622","type":"journal-article","created":{"date-parts":[[2025,7,11]],"date-time":"2025-07-11T07:00:15Z","timestamp":1752217215000},"page":"e005622","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":4,"title":["Evaluating the role of lipopolysaccharides in the joint: fibronectin as a novel protective mechanism"],"prefix":"10.1136","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9743-0335","authenticated-orcid":false,"given":"Kajetana","family":"Bevc","sequence":"first","affiliation":[{"name":"D-HEST, ETH Zurich, Z\u00fcrich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shipin","family":"Zhang","sequence":"additional","affiliation":[{"name":"D-HEST, ETH Zurich, 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