{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T09:05:40Z","timestamp":1789981540950,"version":"4.0.1"},"reference-count":34,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T00:00:00Z","timestamp":1789776000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"State Key Laboratory of Traditional Chinese Medicine Syndrome Postgraduate Program","award":["SKLKY2024A0003"],"award-info":[{"award-number":["SKLKY2024A0003"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background\/Objects: Knee osteoarthritis (KOA) is characterized by pain and progressive cartilage damage, but the underlying molecular mechanisms remain incompletely understood. This study aimed to identify candidate genes through pain-related screening in KOA and explore the potential mechanism by which Vitexin alleviates cartilage damage. Methods: Transcriptomic analysis was performed on peripheral blood samples from control and KOA model mice, and differentially expressed genes were intersected with pain-related genes to identify candidate targets. GO enrichment analysis was subsequently performed to explore their potential biological functions. The role of F3 in KOA was further investigated in vivo using F3-targeting siRNA, followed by VEGFA rescue experiments to evaluate its association with CD31-positive vascular changes. Safranin O\/Fast Green staining and immunofluorescence staining for F3, CD31, and COL2A1 were used to assess cartilage damage and angiogenesis. Finally, Vitexin was administered to KOA mice to investigate its potential effects on F3-associated pathological changes. Results: Integration of transcriptomic data with pain-related genes identified F3 and F8 as candidate genes in KOA. Exploratory GO analysis indicated that F3 was annotated to several angiogenesis-related biological processes. F3 protein expression was markedly increased in the tibial plateau of KOA mice. F3 knockdown reduced CD31 expression, restored COL2A1 expression and cartilage proteoglycan content, and attenuated cartilage damage. VEGFA administration reversed the F3 knockdown-induced reduction in CD31-positive vascular signals and the associated improvement in cartilage damage without restoring F3 expression, suggesting that vascular changes may represent a downstream process associated with F3. Furthermore, Vitexin treatment reduced F3 and CD31 expression, partially restored COL2A1 expression, and alleviated cartilage proteoglycan loss in KOA mice. Conclusions: F3 may contribute to KOA-associated cartilage damage by promoting pathological angiogenesis. Vitexin treatment reduced F3 expression and CD31-positive vascular signals, accompanied by alleviation of cartilage damage. These findings identify F3 as a candidate derived from pain-related gene screening and suggest its potential involvement in pathological angiogenesis and cartilage damage in KOA.<\/jats:p>","DOI":"10.3390\/genes17091148","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T08:03:47Z","timestamp":1789977827000},"page":"1148","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Vitexin Alleviates Knee Osteoarthritis-Associated Cartilage Damage Associated with F3 Modulation"],"prefix":"10.3390","volume":"17","author":[{"given":"Yanxiong","family":"Gu","sequence":"first","affiliation":[{"name":"State Key Laboratory of Traditional Chinese Medicine Syndrome\/Guangzhou University of Chinese Medicine, Guangzhou 510405, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"}]},{"given":"Minshi","family":"Xiao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Traditional Chinese Medicine Syndrome\/Guangzhou University of Chinese Medicine, Guangzhou 510405, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Ziyue","family":"Wu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Traditional Chinese Medicine Syndrome\/Guangzhou University of Chinese Medicine, Guangzhou 510405, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"validation","vocabulary":"credit"}]},{"given":"Yunuo","family":"Shi","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Traditional Chinese Medicine Syndrome\/Guangzhou University of Chinese Medicine, Guangzhou 510405, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"formal-analysis","vocabulary":"credit"}]},{"given":"Wenhui","family":"Geng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Traditional Chinese Medicine Syndrome\/Guangzhou University of Chinese Medicine, Guangzhou 510405, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-original-draft","vocabulary":"credit"}]},{"given":"Xingxiaoyu","family":"Lin","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Traditional Chinese Medicine Syndrome\/Guangzhou University of Chinese Medicine, Guangzhou 510405, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"}]},{"given":"Xiaoqiang","family":"Yang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Traditional Chinese Medicine Syndrome\/Guangzhou University of Chinese Medicine, Guangzhou 510405, China"},{"name":"The Third Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou 510405, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"100587","DOI":"10.1016\/j.eclinm.2020.100587","article-title":"Global, regional prevalence, incidence and risk factors of knee osteoarthritis in population-based studies","volume":"29\u201330","author":"Cui","year":"2020","journal-title":"eClinicalMedicine"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3796","DOI":"10.1038\/s41598-023-30727-4","article-title":"Association of general and central obesity, and their changes with risk of knee osteoarthritis: A nationwide population-based cohort study","volume":"13","author":"Park","year":"2023","journal-title":"Sci. Rep."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"152544","DOI":"10.1016\/j.semarthrit.2024.152544","article-title":"Metabolic syndrome, radiographic osteoarthritis progression and chronic pain of the knee among men and women from the general population: The Rotterdam study","volume":"69","author":"Szilagyi","year":"2024","journal-title":"Semin. Arthritis Rheum."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Li, E., Tan, J., Xu, K., Pan, Y., and Xu, P. (2024). Global burden and socioeconomic impact of knee osteoarthritis: A comprehensive analysis. Front. Med., 11.","DOI":"10.3389\/fmed.2024.1323091"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Chen, X., Tang, H., Lin, J., and Zeng, R. (2023). Temporal trends in the disease burden of osteoarthritis from 1990 to 2019, and projections until 2030. PLoS ONE, 18, Correction in PLoS ONE 2025, 20, e333919.","DOI":"10.1371\/journal.pone.0333919"},{"key":"ref_6","first-page":"e1759","article-title":"Baseline clinical characteristics of predicted structural and pain progressors in the IMI-APPROACH knee OA cohort","volume":"7","author":"Ladel","year":"2021","journal-title":"RMD Open"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1697","DOI":"10.1002\/art.34453","article-title":"Osteoarthritis: A disease of the joint as an organ","volume":"64","author":"Loeser","year":"2012","journal-title":"Arthritis Rheum."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1038\/s41584-023-01067-4","article-title":"Engineering approaches for RNA-based and cell-based osteoarthritis therapies","volume":"20","author":"DeJulius","year":"2024","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"10909","DOI":"10.2147\/DDDT.S564907","article-title":"Drug Delivery Systems Targeting the Knee Microenvironment: A Prospective Strategy for Knee Osteoarthritis Treatment","volume":"19","author":"Xia","year":"2025","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"7459","DOI":"10.2147\/JIR.S518829","article-title":"Therapeutic Effects of Fire Needling Acupuncture on Pain Relief and Cartilage Protection in MIA-Induced Knee Osteoarthritis Rats: The Role of Macrophage Polarization in Synovium and Angiogenesis in Subchondral Bone","volume":"18","author":"Wei","year":"2025","journal-title":"J. Inflamm. Res."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Yan, W., Cheng, J., and Xu, B. (2025). Dietary Flavonoids Vitexin and Isovitexin: New Insights into Their Functional Roles in Human Health and Disease Prevention. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26146997"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"5222","DOI":"10.1002\/ptr.70097","article-title":"Pharmacological Diversity of Flavonoids and Their Clinical Application Prospects in Neurological Disorders","volume":"39","author":"Cheng","year":"2025","journal-title":"Phytother. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"176848","DOI":"10.1016\/j.ejphar.2024.176848","article-title":"Vitexin attenuates neuropathic pain by regulating astrocyte autophagy flux and polarization via the S1P\/ S1PR1-PI3K\/ Akt axis","volume":"981","author":"Huang","year":"2024","journal-title":"Eur. J. Pharmacol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"114877","DOI":"10.1016\/j.intimp.2025.114877","article-title":"Vitexin mitigates AIM2 inflammasome-mediated mitochondrial dysfunction and neuroinflammation in chronic constriction injury induced neuropathy model","volume":"158","author":"Pal","year":"2025","journal-title":"Int. Immunopharmacol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"109961","DOI":"10.1016\/j.neuropharm.2024.109961","article-title":"Examination of the effects of vitexin and vitexin-loaded solid lipid nanoparticles on neuropathic pain and possible mechanisms of action","volume":"253","author":"Eken","year":"2024","journal-title":"Neuropharmacology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"5551","DOI":"10.1002\/ptr.70410","article-title":"Vitexin Alleviates Osteoarthritis Progression Through Sirtuin 3-Mediated Inhibition of Chondrocyte Ferroptosis and Mitochondrial Dysfunction","volume":"40","author":"Wu","year":"2026","journal-title":"Phytother. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2581","DOI":"10.1039\/D2BM02038F","article-title":"Nano-formulations for bone-specific delivery of siRNA for CrkII silencing-induced regulation of bone formation and resorption to maximize therapeutic potential for bone-related diseases","volume":"11","author":"Seong","year":"2023","journal-title":"Biomater. Sci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.joca.2025.11.007","article-title":"Imeglimin, a novel antidiabetic agent related to metformin, attenuates knee osteoarthritis development and progression through AMPK activation and NF-\u03baB signaling inhibition","volume":"34","author":"Hyodo","year":"2026","journal-title":"Osteoarthr. Cartil."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e47","DOI":"10.1093\/nar\/gkv007","article-title":"limma powers differential expression analyses for RNA-sequencing and microarray studies","volume":"43","author":"Ritchie","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_20","first-page":"100141","article-title":"clusterProfiler 4.0: A universal enrichment tool for interpreting omics data","volume":"2","author":"Wu","year":"2021","journal-title":"Innovation"},{"key":"ref_21","first-page":"100722","article-title":"Thirteen years of clusterProfiler","volume":"5","author":"Yu","year":"2024","journal-title":"Innovation"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1089\/omi.2011.0118","article-title":"clusterProfiler: An R package for comparing biological themes among gene clusters","volume":"16","author":"Yu","year":"2012","journal-title":"Omics J. Integr. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/S0168-9525(97)01103-7","article-title":"GeneCards: Integrating information about genes, proteins and diseases","volume":"13","author":"Rebhan","year":"1997","journal-title":"Trends Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.jphys.2024.11.011","article-title":"Clinimetrics: The Knee injury and Osteoarthritis Outcome Score (KOOS)","volume":"71","author":"Collins","year":"2025","journal-title":"J. Physiother."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e18460","DOI":"10.1111\/jcmm.18460","article-title":"AAV mediated repression of Neat1 lncRNA combined with F8 gene augmentation mitigates pathological mediators of joint disease in haemophilia","volume":"28","author":"Sarangi","year":"2024","journal-title":"J. Cell. Mol. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e25518","DOI":"10.1097\/MD.0000000000025518","article-title":"Acquired hemophilia A associated with Epstein-Barr-virus-associated T\/natural killer-cell lymphoproliferative disease: A case report","volume":"100","author":"Yamamoto","year":"2021","journal-title":"Medicine"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3706","DOI":"10.1182\/bloodadvances.2025016474","article-title":"Patient anti-FVIII drug antibodies bind preferentially to a subset of FVIII covalent states","volume":"9","author":"Butera","year":"2025","journal-title":"Blood Adv."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1038\/nature10893","article-title":"Tissue factor and PAR1 promote microbiota-induced intestinal vascular remodelling","volume":"483","author":"Reinhardt","year":"2012","journal-title":"Nature"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3963","DOI":"10.1158\/0008-5472.CAN-12-1690","article-title":"Endothelial cell protein C receptor opposes mesothelioma growth driven by tissue factor","volume":"73","author":"Keshava","year":"2013","journal-title":"Cancer Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"C1596","DOI":"10.1152\/ajpcell.00563.2025","article-title":"Protease-activated receptor 1-mediated matrix metalloprotease signaling in sensory neurons","volume":"329","author":"Williams","year":"2025","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1016\/j.jpain.2023.01.003","article-title":"Activation of Protease-Activated Receptor-1 Causes Chronic Pain in Lupus-Prone Mice Via Suppressing Spinal Glial Glutamate Transporter Function and Enhancing Glutamatergic Synaptic Activity","volume":"24","author":"Li","year":"2023","journal-title":"J. Pain"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2652","DOI":"10.1158\/2159-8290.CD-22-1467","article-title":"Oncogenic KRAS Drives Lipofibrogenesis to Promote Angiogenesis and Colon Cancer Progression","volume":"13","author":"Hsu","year":"2023","journal-title":"Cancer Discov."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Sun, Y., Xiang, X., Yang, J., Peng, J.-L., and He, H.-C. (2025). Platelet-rich plasma improves pain and function in knee osteoarthritis: A retrospective study. Front. Physiol., 16.","DOI":"10.3389\/fphys.2025.1678037"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"560506","DOI":"10.2147\/JPR.S560506","article-title":"Electroacupuncture Alleviates KOA-Induced Pain and Cartilage Degeneration via NGF\/TrkA Pathway","volume":"19","author":"Fu","year":"2026","journal-title":"J. Pain Res."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/9\/1148\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T08:23:48Z","timestamp":1789979028000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/9\/1148"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,19]]},"references-count":34,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["genes17091148"],"URL":"https:\/\/doi.org\/10.3390\/genes17091148","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,19]]}}}