{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,6]],"date-time":"2026-06-06T07:28:38Z","timestamp":1780730918727,"version":"3.54.1"},"reference-count":95,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2023,1,26]],"date-time":"2023-01-26T00:00:00Z","timestamp":1674691200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"The Doctoral Programme in Science, Technology and Computing (SCITECO),"},{"name":"Strategic funding of the University of Eastern Finland"},{"DOI":"10.13039\/501100002341","name":"Academy of Finland","doi-asserted-by":"crossref","award":["334773 \u2013 under the frame of ERA PerMed, 324529"],"award-info":[{"award-number":["334773 \u2013 under the frame of ERA PerMed, 324529"]}],"id":[{"id":"10.13039\/501100002341","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Novo Nordisk Foundation (the Center for Mathematical Modeling of Knee Osteoarthritis","award":["NNF21OC0065373"],"award-info":[{"award-number":["NNF21OC0065373"]}]},{"DOI":"10.13039\/100008969","name":"Alfred Kordelin Foundation","doi-asserted-by":"crossref","award":["190317"],"award-info":[{"award-number":["190317"]}],"id":[{"id":"10.13039\/100008969","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100022768","name":"Maire Lisko Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100022768","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Sigrid Juselius Foundation"},{"DOI":"10.13039\/501100017643","name":"Saastamoinen Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100017643","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100008413","name":"Instrumentarium Science Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100008413","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001862","name":"the Swedish Research Council","doi-asserted-by":"crossref","award":["2019-00953 - under the frame of Eramerped"],"award-info":[{"award-number":["2019-00953 - under the frame of Eramerped"]}],"id":[{"id":"10.13039\/501100001862","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>Osteoarthritis (OA) is a common musculoskeletal disease that leads to deterioration of articular cartilage, joint pain, and decreased quality of life. When OA develops after a joint injury, it is designated as post-traumatic OA (PTOA). The etiology of PTOA remains poorly understood, but it is known that proteoglycan (PG) loss, cell dysfunction, and cell death in cartilage are among the first signs of the disease. These processes, influenced by biomechanical and inflammatory stimuli, disturb the normal cell-regulated balance between tissue synthesis and degeneration. Previous computational mechanobiological models have not explicitly incorporated the cell-mediated degradation mechanisms triggered by an injury that eventually can lead to tissue-level compositional changes. Here, we developed a 2-D mechanobiological finite element model to predict necrosis, apoptosis following excessive production of reactive oxygen species (ROS), and inflammatory cytokine (interleukin-1)-driven apoptosis in cartilage explant. The resulting PG loss over 30 days was simulated. Biomechanically triggered PG degeneration, associated with cell necrosis, excessive ROS production, and cell apoptosis, was predicted to be localized near a lesion, while interleukin-1 diffusion-driven PG degeneration was manifested more globally. Interestingly, the model also showed proteolytic activity and PG biosynthesis closer to the levels of healthy tissue when pro-inflammatory cytokines were rapidly inhibited or cleared from the culture medium, leading to partial recovery of PG content. The numerical predictions of cell death and PG loss were supported by previous experimental findings. Furthermore, the simulated ROS and inflammation mechanisms had longer-lasting effects (over 3 days) on the PG content than localized necrosis. The mechanobiological model presented here may serve as a numerical tool for assessing early cartilage degeneration mechanisms and the efficacy of interventions to mitigate PTOA progression.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1010337","type":"journal-article","created":{"date-parts":[[2023,1,26]],"date-time":"2023-01-26T13:24:20Z","timestamp":1674739460000},"page":"e1010337","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":28,"title":["Injury-related cell death and proteoglycan loss in articular cartilage: Numerical model combining necrosis, reactive oxygen species, and inflammatory cytokines"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6063-6914","authenticated-orcid":true,"given":"Joonas P.","family":"Kosonen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atte S. 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K.","family":"Korhonen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petri","family":"Tanska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,1,26]]},"reference":[{"key":"pcbi.1010337.ref001","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1002\/jor.21359","article-title":"Post-traumatic osteoarthritis: Improved understanding and opportunities for early intervention","volume":"29","author":"DD Anderson","year":"2011","journal-title":"J Orthop Res"},{"key":"pcbi.1010337.ref002","doi-asserted-by":"crossref","first-page":"1825","DOI":"10.1016\/j.joca.2015.08.015","article-title":"Inflammation in joint injury and post-traumatic osteoarthritis","volume":"23","author":"J Lieberthal","year":"2015","journal-title":"Osteoarthr 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Kinetics of oxygen utilization","volume":"217","author":"B Chance","year":"1955","journal-title":"J Biol Chem"},{"key":"pcbi.1010337.ref054","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.freeradbiomed.2018.08.038","article-title":"Reactive oxygen species, aging and articular cartilage homeostasis","volume":"132","author":"JA Bolduc","year":"2019","journal-title":"Free Radic Biol Med"},{"key":"pcbi.1010337.ref055","doi-asserted-by":"crossref","first-page":"1890","DOI":"10.2106\/JBJS.H.00545","article-title":"N-acetylcysteine inhibits post-impact chondrocyte death in osteochondral explants","volume":"91","author":"JA Martin","year":"2009","journal-title":"J Bone Jt Surg\u2014Ser A"},{"key":"pcbi.1010337.ref056","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1007\/s000110050478","article-title":"Effect of hydrogen peroxide on the metabolism of articular chondrocytes","volume":"48","author":"S Asada","year":"1999","journal-title":"Inflamm Res"},{"key":"pcbi.1010337.ref057","doi-asserted-by":"crossref","first-page":"9177","DOI":"10.12659\/MSM.913726","article-title":"Effects of hesperidin on H2O2-treated chondrocytes and cartilage in a rat osteoarthritis model","volume":"24","author":"G Gao","year":"2018","journal-title":"Med Sci Monit"},{"key":"pcbi.1010337.ref058","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.joca.2003.11.004","article-title":"Ultrastructural quantification of cell death after injurious compression of bovine calf articular cartilage","volume":"12","author":"P Patwari","year":"2004","journal-title":"Osteoarthr Cartil"},{"key":"pcbi.1010337.ref059","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1016\/S1063-4584(03)00156-0","article-title":"Influence of pro-inflammatory (IL-1\u03b1, IL-6, TNF-\u03b1, IFN-\u03b3) and anti-inflammatory (IL-4) cytokines on chondrocyte function.","volume":"11","author":"AJ Schuerwegh","year":"2003","journal-title":"Osteoarthr Cartil."},{"key":"pcbi.1010337.ref060","doi-asserted-by":"crossref","first-page":"107905","DOI":"10.1016\/j.intimp.2021.107905","article-title":"International Immunopharmacology Inflammatory factors are crucial for the pathogenesis of post-traumatic osteoarthritis confirmed by a novel porcine model: \u201cIdealized\u201d anterior cruciate ligament reconstruction\u201d and gait analysis","volume":"99","author":"R Zhao","year":"2021","journal-title":"Int Immunopharmacol"},{"key":"pcbi.1010337.ref061","doi-asserted-by":"crossref","first-page":"1816","DOI":"10.1002\/art.39146","article-title":"Changes in cytokines and aggrecan ARGS neoepitope in synovial fluid and serum and in C-terminal crosslinking telopeptide of type II collagen and N-terminal crosslinking telopeptide of type i collagen in urine over five years after anterior cruciate ligame","volume":"67","author":"A Struglics","year":"2015","journal-title":"Arthritis Rheumatol"},{"key":"pcbi.1010337.ref062","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1111\/j.1749-6632.1999.tb07700.x","article-title":"Physical and biological regulation of proteoglycan turnover around chondrocytes in cartilage explants. 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ECM-destructive enzymes by N-acetyl cysteine","volume":"24","author":"J Riegger","year":"2016","journal-title":"Osteoarthr Cartil"},{"key":"pcbi.1010337.ref072","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1016\/j.joca.2006.01.005","article-title":"Cytokines, tumor necrosis factor-\u03b1 and interleukin-1\u03b2, differentially regulate apoptosis in osteoarthritis cultured human chondrocytes","volume":"14","author":"MJ L\u00f3pez-Armada","year":"2006","journal-title":"Osteoarthr Cartil"},{"key":"pcbi.1010337.ref073","doi-asserted-by":"crossref","first-page":"2985","DOI":"10.1002\/art.24857","article-title":"Mechanical injury potentiates proteoglycan catabolism induced by interleukin-6 with soluble interleukin-6 receptor and tumor necrosis factor \u03b1 in immature bovine and adult human articular cartilage","volume":"60","author":"Y Sui","year":"2009","journal-title":"Arthritis Rheum"},{"key":"pcbi.1010337.ref074","first-page":"1","article-title":"Early changes in osteochondral tissues in a rabbit model of post-traumatic osteoarthritis","author":"L Huang","year":"2021","journal-title":"J Orthop Res"},{"key":"pcbi.1010337.ref075","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1186\/ar615","article-title":"Differential recovery of glycosaminoglycan after IL-1-induced degradation of bovine articular cartilage depends on degree of degradation","volume":"5","author":"A Williams","year":"2003","journal-title":"Arthritis Res Ther"},{"key":"pcbi.1010337.ref076","first-page":"75","article-title":"Chondrocyte apoptosis induced by nitric oxide","volume":"146","author":"FJ Blanco","year":"1995","journal-title":"Am J Pathol"},{"key":"pcbi.1010337.ref077","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1016\/j.joca.2004.02.012","article-title":"Increased stromelysin-1 (MMP-3), proteoglycan degradation (3B3- and 7D4) and collagen damage in cyclically load-injured articular cartilage","volume":"12","author":"PM Lin","year":"2004","journal-title":"Osteoarthr Cartil"},{"key":"pcbi.1010337.ref078","first-page":"133","article-title":"A fully coupled poroelastic reactive-transport model of cartilage","volume":"5","author":"L Zhang","year":"2008","journal-title":"MCB Mol Cell Biomech"},{"key":"pcbi.1010337.ref079","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.abb.2006.10.007","article-title":"The effect of cyclic deformation and solute binding on solute transport in cartilage","volume":"457","author":"L Zhang","year":"2007","journal-title":"Arch Biochem Biophys"},{"key":"pcbi.1010337.ref080","doi-asserted-by":"crossref","first-page":"1933","DOI":"10.1016\/j.joca.2013.08.021","article-title":"Moderate dynamic compression inhibits pro-catabolic response of cartilage to mechanical injury, tumor necrosis factor-\u03b1 and interleukin-6, but accentuates degradation above a strain threshold","volume":"21","author":"Y Li","year":"2013","journal-title":"Osteoarthr 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Mechanobiol"},{"key":"pcbi.1010337.ref084","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1016\/j.joca.2014.04.010","article-title":"Site-dependent changes in structure and function of lapine articular cartilage 4 weeks after anterior cruciate ligament transection","volume":"22","author":"JTA M\u00e4kel\u00e4","year":"2014","journal-title":"Osteoarthr Cartil"},{"key":"pcbi.1010337.ref085","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/j.actbio.2021.08.001","article-title":"High-resolution infrared microspectroscopic characterization of cartilage cell microenvironment","volume":"134","author":"A Linus","year":"2021","journal-title":"Acta Biomater"},{"key":"pcbi.1010337.ref086","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.matbio.2018.05.008","article-title":"Osteoarthritis as a disease of the cartilage pericellular matrix","volume":"71\u201372","author":"F Guilak","year":"2018","journal-title":"Matrix Biol"},{"key":"pcbi.1010337.ref087","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/j.actbio.2020.05.005","article-title":"Early changes in cartilage pericellular matrix micromechanobiology portend the onset of post-traumatic osteoarthritis","volume":"111","author":"DR Chery","year":"2020","journal-title":"Acta Biomater"},{"key":"pcbi.1010337.ref088","doi-asserted-by":"crossref","first-page":"1166","DOI":"10.1007\/s10439-014-1164-8","article-title":"Time Evolution of Deformation in a Human Cartilage Under Cyclic Loading","volume":"43","author":"L Zhang","year":"2015","journal-title":"Ann Biomed Eng"},{"key":"pcbi.1010337.ref089","doi-asserted-by":"crossref","first-page":"106185","DOI":"10.1016\/j.triboint.2020.106185","article-title":"A coupled contact model of cartilage lubrication in the mixed-mode regime under static compression","volume":"145","author":"JJ Liao","year":"2020","journal-title":"Tribol 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Rheumatol"},{"key":"pcbi.1010337.ref093","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/srep37538","article-title":"Quantitative Evaluation of the Mechanical Risks Caused by Focal Cartilage Defects in the Knee","volume":"6","author":"MS Ven\u00e4l\u00e4inen","year":"2016","journal-title":"Sci Rep"},{"key":"pcbi.1010337.ref094","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-020-59602-2","article-title":"EMG-Assisted Muscle Force Driven Finite Element Model of the Knee Joint with Fibril-Reinforced Poroelastic Cartilages and Menisci","volume":"10","author":"A Esrafilian","year":"2020","journal-title":"Sci Rep"},{"key":"pcbi.1010337.ref095","doi-asserted-by":"crossref","first-page":"1505","DOI":"10.1002\/jor.25177","article-title":"Shear strain and inflammation-induced fixed charge density loss in the knee joint cartilage following ACL injury and reconstruction: A computational study","volume":"40","author":"GA Orozco","year":"2022","journal-title":"J 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