{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T18:22:09Z","timestamp":1785435729908,"version":"3.56.0"},"reference-count":50,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T00:00:00Z","timestamp":1780531200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["20K09500"],"award-info":[{"award-number":["20K09500"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"award":["20K09500"],"award-info":[{"award-number":["20K09500"]}],"id":[{"id":"https:\/\/ror.org\/00hhkn466","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CIMB"],"abstract":"<jats:p>Osteoarthritis (OA) is highly prevalent worldwide. Fibronectin (FN) has been associated with OA pathology; however, its role remains unexplored. In this study, we hypothesized that FNIII14 induces chondrocyte apoptosis by inactivating \u03b21 integrin and aimed to clarify the role of FNIII14 in OA pathology. Immunohistochemistry, immunofluorescence, flow cytometry, a 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay, a terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling assay, real-time quantitative polymerase chain reaction, and Western blotting were performed using cartilage obtained from patients who underwent total knee arthroplasty. In a mouse model, FNIII14 or phosphate-buffered saline was administered to the knees, and cartilage degeneration and synovitis were evaluated using the Mankin and Synovitis scores, respectively. Statistical significance was determined using the Mann\u2013Whitney U or Kruskal\u2013Wallis test (p &lt; 0.05). FNIII14 was detected in highly degenerated OA cartilage, with decreased \u03b21 integrin activity, suppressed cell proliferation, and induced apoptosis in chondrocytes. FNIII14 decreased the gene expression of cartilage-specific markers and anabolic factors and increased inflammatory cytokine gene expression and phosphorylation of extracellular signal-regulated protein kinase-1\/2. FNIII14 induced cartilage degeneration in mouse knees with almost no synovitis. Regulation of FNIII14 production and action may play an important role in suppressing cartilage degeneration in human OA.<\/jats:p>","DOI":"10.3390\/cimb48060594","type":"journal-article","created":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T01:23:21Z","timestamp":1780622601000},"page":"594","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Fibronectin Peptide FNIII14 Enhances Progressive Cartilage Degeneration in Osteoarthritis by Inducing Chondrocyte Apoptosis"],"prefix":"10.3390","volume":"48","author":[{"given":"Fumihiro","family":"Nishimura","sequence":"first","affiliation":[{"name":"Department of Orthopedic Surgery, Graduate School of Medicine, Mie University, 2-174 Edobashi, Mie, Tsu City 514-8507, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manabu","family":"Sasada","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Chiba, Noda City 278-8510, Japan"},{"name":"Clinical Research Center in Hiroshima, Hiroshima University Hospital, 1-2-3 Kasumi, Hiroshima, Minami-Ku 734-8551, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fumio","family":"Fukai","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Chiba, Noda City 278-8510, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyoko","family":"Imanaka-Yoshida","sequence":"additional","affiliation":[{"name":"Department of Pathology and Matrix Biology, Graduate School of Medicine, Mie University, 2-174 Edobashi, Mie, Tsu City 514-8507, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihiro","family":"Sudo","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, Graduate School of Medicine, Mie University, 2-174 Edobashi, Mie, Tsu City 514-8507, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7948-2003","authenticated-orcid":false,"given":"Masahiro","family":"Hasegawa","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, Graduate School of Medicine, Mie University, 2-174 Edobashi, Mie, Tsu City 514-8507, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1745","DOI":"10.1016\/S0140-6736(19)30417-9","article-title":"Osteoarthritis","volume":"393","author":"Hunter","year":"2019","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1172","DOI":"10.1002\/art.42089","article-title":"Prevalence Trends of Site-Specific Osteoarthritis from 1990 to 2019: Findings from the Global Burden of Disease Study 2019","volume":"74","author":"Long","year":"2022","journal-title":"Arthritis Rheumatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.joca.2020.10.006","article-title":"Osteoarthritis year in review 2020: Biology","volume":"29","year":"2021","journal-title":"Osteoarthr. Cartil."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.bcp.2019.02.036","article-title":"Chondrocyte dedifferentiation and osteoarthritis (OA)","volume":"165","author":"Charlier","year":"2019","journal-title":"Biochem. Pharmacol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3103","DOI":"10.1021\/ja01189a080","article-title":"Preparation and properties of serum and plasma proteins; the separation of purified fibrinogen from fraction I of human plasma","volume":"70","author":"Morrison","year":"1948","journal-title":"J. Am. Chem. Soc."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1016\/0019-2791(76)90203-2","article-title":"Immunological interspecies cross-reactions of fibroblast surface antigen (fibronectin)","volume":"13","author":"Kuusela","year":"1976","journal-title":"Immunochemistry"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1217","DOI":"10.1073\/pnas.73.4.1217","article-title":"Cell surface protein partially restores morphology, adhesiveness, and contact inhibition of movement to transformed fibroblasts","volume":"73","author":"Yamada","year":"1976","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3861","DOI":"10.1242\/jcs.00059","article-title":"Fibronectin at a glance","volume":"115","author":"Pankov","year":"2002","journal-title":"J. Cell Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1002\/jor.1100040403","article-title":"Incorporation of purified plasma fibronectin into explants of articular cartilage from disease-free and osteoarthritic canine joints","volume":"4","author":"Lust","year":"1986","journal-title":"J. Orthop. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/S0049-0172(05)80010-1","article-title":"Fibronectin, cartilage, and osteoarthritis","volume":"22","author":"Chevalier","year":"1993","journal-title":"Semin. Arthritis Rheum."},{"key":"ref_11","first-page":"189","article-title":"Identification of the anti-adhesive site buried within the heparin-binding domain of fibronectin","volume":"121","author":"Fukai","year":"1997","journal-title":"J. Biochem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"7138","DOI":"10.1021\/bi992670r","article-title":"Interaction with heparin and matrix metalloproteinase 2 cleavage expose a cryptic anti-adhesive site of fibronectin","volume":"39","author":"Watanabe","year":"2000","journal-title":"Biochemistry"},{"key":"ref_13","first-page":"2455","article-title":"A new type of antimetastatic peptide derived from fibronectin","volume":"8","author":"Kato","year":"2002","journal-title":"Clin. Cancer Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.bbrc.2020.12.050","article-title":"Anoikis resistance conferred by tenascin-C-derived peptide TNIIIA2 and its disruption by integrin inactivation","volume":"536","author":"Fujita","year":"2021","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1074","DOI":"10.3892\/ijmm.2015.2114","article-title":"Integrin-\u03b21 regulates chondrocyte proliferation and apoptosis through the upregulation of GIT1 expression","volume":"35","author":"Zhang","year":"2015","journal-title":"Int. J. Mol. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1367s","DOI":"10.1177\/1947603520912300","article-title":"TNIIIA2, The Peptide of Tenascin-C, as a Candidate for Preventing Articular Cartilage Degeneration","volume":"13","author":"Hattori","year":"2021","journal-title":"Cartilage"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"16037","DOI":"10.1074\/jbc.M111.308122","article-title":"Eukaryotic translation elongation factor 1A induces anoikis by triggering cell detachment","volume":"287","author":"Itagaki","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"523","DOI":"10.2106\/00004623-197153030-00009","article-title":"Biochemical and metabolic abnormalities in articular cartilage from osteo-arthritic human hips. II. Correlation of morphology with biochemical and metabolic data","volume":"53","author":"Mankin","year":"1971","journal-title":"J. Bone Jt. Surg. Am."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1111\/j.1365-2559.2006.02508.x","article-title":"Synovitis score: Discrimination between chronic low-grade and high-grade synovitis","volume":"49","author":"Krenn","year":"2006","journal-title":"Histopathology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1002\/art.1780270811","article-title":"Characterization of synovial fluid fibronectin from patients with rheumatic inflammatory diseases and healthy subjects","volume":"27","author":"Carnemolla","year":"1984","journal-title":"Arthritis Rheum."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1136\/ard.46.11.809","article-title":"An immunohistochemical study of fibronectin in human osteoarthritic and disease free articular cartilage","volume":"46","author":"Jones","year":"1987","journal-title":"Ann. Rheum. Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"117","DOI":"10.2106\/00004623-200300002-00016","article-title":"Gene expression in chondrocytes assessed with use of microarrays","volume":"85-A","author":"Aigner","year":"2003","journal-title":"J. Bone Jt. Surg. Am."},{"key":"ref_23","first-page":"603","article-title":"MMP-2\/gelatinase A is a gene product of human adult articular chondrocytes and is increased in osteoarthritic cartilage","volume":"22","author":"Duerr","year":"2004","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.bbagen.2004.08.009","article-title":"A fibronectin fragment induces tumor necrosis factor production of rat basophilic leukemia cells","volume":"1675","author":"Kamiya","year":"2004","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"4960","DOI":"10.18632\/oncotarget.27131","article-title":"Inactivation of beta1 integrin induces proteasomal degradation of Myc oncoproteins","volume":"10","author":"Sasada","year":"2019","journal-title":"Oncotarget"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1038\/s41584-024-01130-8","article-title":"Integrin signalling in joint development, homeostasis and osteoarthritis","volume":"20","author":"Miao","year":"2024","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Arai, Y., Cha, R., Nakagawa, S., Inoue, A., Nakamura, K., and Takahashi, K. (2024). Cartilage Homeostasis under Physioxia. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25179398"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Jin, H., Jiang, S., Wang, R., Zhang, Y., Dong, J., and Li, Y. (2021). Mechanistic Insight Into the Roles of Integrins in Osteoarthritis. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.693484"},{"key":"ref_29","unstructured":"Kamkin, A., and Kiseleva, I. (2005). Functional Roles of Mechanosensitive Ion Channels, \u00df1 Integrins and Kinase Cascades in Chondrocyte Mechanotransduction. Mechanosensitivity in Cells and Tissues, Academia Publishing House Ltd."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.matbio.2014.08.007","article-title":"Integrins and chondrocyte-matrix interactions in articular cartilage","volume":"39","author":"Loeser","year":"2014","journal-title":"Matrix Biol."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Gao, W., Hasan, H., Anderson, D.E., and Lee, W. (2022). The Role of Mechanically-Activated Ion Channels Piezo1, Piezo2, and TRPV4 in Chondrocyte Mechanotransduction and Mechano-Therapeutics for Osteoarthritis. Front. Cell Dev. Biol., 10.","DOI":"10.3389\/fcell.2022.885224"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"26035","DOI":"10.3390\/ijms161125943","article-title":"Chondrocyte Apoptosis in the Pathogenesis of Osteoarthritis","volume":"16","author":"Hwang","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1038\/emm.2004.31","article-title":"Interleukin-1beta stimulates matrix metalloproteinase-2 expression via a prostaglandin E2-dependent mechanism in human chondrocytes","volume":"36","author":"Choi","year":"2004","journal-title":"Exp. Mol. Med."},{"key":"ref_34","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_35","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.ceb.2019.07.008","article-title":"SOX9 in cartilage development and disease","volume":"61","author":"Lefebvre","year":"2019","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1248\/bpb.30.891","article-title":"Antiadhesive sites present in the fibronectin type III-like repeats of human plasma fibronectin","volume":"30","author":"Miura","year":"2007","journal-title":"Biol. Pharm. Bull."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1016\/j.joca.2008.02.015","article-title":"The cartilage chondrolytic mechanism of fibronectin fragments involves MAP kinases: Comparison of three fragments and native fibronectin","volume":"16","author":"Ding","year":"2008","journal-title":"Osteoarthr. Cartil."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1038\/s41580-020-0255-7","article-title":"ERK signalling: A master regulator of cell behaviour, life and fate","volume":"21","author":"Lavoie","year":"2020","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1006\/bbrc.1998.9256","article-title":"Increased MAPK activity and MKP-1 overexpression in human gastric adenocarcinoma","volume":"250","author":"Bang","year":"1998","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1038\/nrd4281","article-title":"Targeting RAS-ERK signalling in cancer: Promises and challenges","volume":"13","author":"Samatar","year":"2014","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1016\/j.cell.2012.06.034","article-title":"ERK inhibition rescues defects in fate specification of Nf1-deficient neural progenitors and brain abnormalities","volume":"150","author":"Wang","year":"2012","journal-title":"Cell"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1146\/annurev-genom-091212-153523","article-title":"The RASopathies","volume":"14","author":"Rauen","year":"2013","journal-title":"Annu. Rev. Genom. Hum. Genet."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"S145","DOI":"10.1097\/01.blo.0000143802.41885.50","article-title":"Protein kinases in chondrocyte signaling and osteoarthritis","volume":"427","author":"Malemud","year":"2004","journal-title":"Clin. Orthop. Relat. Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"13289","DOI":"10.1074\/jbc.M010859200","article-title":"Inhibition of mitogen-activated protein kinase kinase induces apoptosis of human chondrocytes","volume":"276","author":"Shakibaei","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1332","DOI":"10.1074\/jbc.M107231200","article-title":"ERK-1\/2 and p38 kinase oppositely regulate nitric oxide-induced apoptosis of chondrocytes in association with p53, caspase-3, and differentiation status","volume":"277","author":"Kim","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"22399","DOI":"10.1074\/jbc.M314118200","article-title":"15-deoxy-delta12,14-prostaglandin J2 inhibits Bay 11-7085-induced sustained extracellular signal-regulated kinase phosphorylation and apoptosis in human articular chondrocytes and synovial fibroblasts","volume":"279","author":"Relic","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Kong, D., Zheng, T., Zhang, M., Wang, D., Du, S., Li, X., Fang, J., and Cao, X. (2013). Static mechanical stress induces apoptosis in rat endplate chondrocytes through MAPK and mitochondria-dependent caspase activation signaling pathways. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0069403"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1284","DOI":"10.1016\/j.joca.2016.02.005","article-title":"Monoiodoacetic acid induces arthritis and synovitis in rats in a dose- and time-dependent manner: Proposed model-specific scoring systems","volume":"24","author":"Udo","year":"2016","journal-title":"Osteoarthr. Cartil."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Krakowski, P., Rejniak, A., Sobczyk, J., and Karpi\u0144ski, R. (2024). Cartilage Integrity: A Review of Mechanical and Frictional Properties and Repair Approaches in Osteoarthritis. Healthcare, 12, Erratum in Healthcare\u00a02025, 13, 3173.","DOI":"10.3390\/healthcare13233173"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1530","DOI":"10.1016\/j.joca.2024.09.011","article-title":"Osteoarthritis year in review 2024: Biomechanics","volume":"32","author":"Ewald","year":"2024","journal-title":"Osteoarthr. Cartil."}],"container-title":["Current Issues in Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1467-3045\/48\/6\/594\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T02:35:33Z","timestamp":1780626933000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1467-3045\/48\/6\/594"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,4]]},"references-count":50,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["cimb48060594"],"URL":"https:\/\/doi.org\/10.3390\/cimb48060594","relation":{},"ISSN":["1467-3045"],"issn-type":[{"value":"1467-3045","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,4]]}}}