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In this study, a glycosaminoglycan (GAG)-mimetic sulfated chitosan (SCS) was synthesized via chemical modification of chitosan by grafting sulfonic acid groups, aiming to address these pathological features simultaneously. The therapeutic potential of SCS in OA was systematically evaluated. In vitro results demonstrated that SCS significantly promoted ECM synthesis in chondrocytes. Tribological analysis further revealed that SCS effectively enhanced cartilage lubrication in OA porcine cartilage, as evidenced by a marked reduction in the coefficient of friction, which decreased by 19% under a 5 N load and by 30% under a 10 N load. PCR analysis showed that SCS treatment significantly upregulated chondrogenic-related genes. In addition, SCS exhibited pronounced anti-inflammatory effects by downregulating the expression of inflammatory and catabolic genes. Importantly, in vivo studies demonstrated that SCS effectively preserved cartilage ECM and alleviated synovitis. Collectively, these findings indicate that SCS can simultaneously promote cartilage matrix regeneration, improve lubrication, and suppress inflammation, thereby effectively alleviating OA progression in a complex pathological environment. This study highlights the potential of SCS as a multifunctional GAG-mimetic biomaterial for osteoarthritis therapy.<\/jats:p>","DOI":"10.3390\/bioengineering13050576","type":"journal-article","created":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T15:45:34Z","timestamp":1779291934000},"page":"576","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Glycosaminoglycan-Mimetic Sulfated Chitosan Promotes Extracellular Matrix Formation and Regulates Inflammation to Alleviate Osteoarthritis"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-9170-5973","authenticated-orcid":false,"given":"Xinye","family":"Chen","sequence":"first","affiliation":[{"name":"The State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China"},{"name":"Key Laboratory for Ultrafine Materials of Ministry of Education, East China University of Science and Technology, Shanghai 200237, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zirui","family":"He","sequence":"additional","affiliation":[{"name":"Key Laboratory for Ultrafine Materials of Ministry of Education, East China University of Science and Technology, Shanghai 200237, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0030-7881","authenticated-orcid":false,"given":"Yuanman","family":"Yu","sequence":"additional","affiliation":[{"name":"Frontiers Science Center for Materiobiology and Dynamic Chemistry, East China University of Science and Technology, Shanghai 200237, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Wang","sequence":"additional","affiliation":[{"name":"The State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China"},{"name":"Key Laboratory for Ultrafine Materials of Ministry of Education, East China University of Science and Technology, Shanghai 200237, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changsheng","family":"Liu","sequence":"additional","affiliation":[{"name":"The State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China"},{"name":"Key Laboratory for Ultrafine Materials of Ministry of Education, East China University of Science and Technology, Shanghai 200237, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1038\/nrrheum.2013.72","article-title":"Post-Traumatic Osteoarthritis: From Mouse Models to Clinical Trials","volume":"9","author":"Little","year":"2013","journal-title":"Nat. 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