{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T03:06:37Z","timestamp":1793847997195,"version":"4.6.1"},"reference-count":74,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2021,7,5]],"date-time":"2021-07-05T00:00:00Z","timestamp":1625443200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Fund for Regional Development (EFRE) and the Fund for Economy and Tourism of Lower Austria","award":["WST3-F-5030664\/003-2017"],"award-info":[{"award-number":["WST3-F-5030664\/003-2017"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Osteoarthritis (OA) is hallmarked by a progressive degradation of articular cartilage. One major driver of OA is inflammation, in which cytokines such as IL-6, TNF-\u03b1 and IL-1\u03b2 are secreted by activated chondrocytes, as well as synovial cells\u2014including macrophages. Intra-articular injection of blood products\u2014such as citrate-anticoagulated plasma (CPRP), hyperacute serum (hypACT), and extracellular vesicles (EVs) isolated from blood products\u2014is gaining increasing importance in regenerative medicine for the treatment of OA. A co-culture system of primary OA chondrocytes and activated M1 macrophages was developed to model an OA joint in order to observe the effects of EVs in modulating the inflammatory environment. Primary OA chondrocytes were obtained from patients undergoing total knee replacement. Primary monocytes obtained from voluntary healthy donors and the monocytic cell line THP-1 were differentiated and activated into proinflammatory M1 macrophages. EVs were isolated by ultracentrifugation and characterized by nanoparticle tracking analysis and Western blot. Gene expression analysis of chondrocytes by RT-qPCR revealed increased type II collagen expression, while cytokine profiling via ELISA showed lower TNF-\u03b1 and IL-1\u03b2 levels associated with EV treatment. In conclusion, the inflammation model provides an accessible tool to investigate the effects of blood products and EVs in the inflammatory context of OA.<\/jats:p>","DOI":"10.3390\/ijms22137224","type":"journal-article","created":{"date-parts":[[2021,7,5]],"date-time":"2021-07-05T22:02:04Z","timestamp":1625522524000},"page":"7224","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Effects of Extracellular Vesicles from Blood-Derived Products on Osteoarthritic Chondrocytes within an Inflammation Model"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3705-0039","authenticated-orcid":false,"given":"Alexander","family":"Otahal","sequence":"first","affiliation":[{"name":"Center for Regenerative Medicine, Danube University Krems, 3500 Krems, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karina","family":"Kramer","sequence":"additional","affiliation":[{"name":"Center for Regenerative Medicine, Danube University Krems, 3500 Krems, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1827-1314","authenticated-orcid":false,"given":"Olga","family":"Kuten-Pella","sequence":"additional","affiliation":[{"name":"OrthoSera GmbH, 3500 Krems, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lukas B.","family":"Moser","sequence":"additional","affiliation":[{"name":"Center for Regenerative Medicine, Danube University Krems, 3500 Krems, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Neubauer","sequence":"additional","affiliation":[{"name":"Center for Regenerative Medicine, Danube University Krems, 3500 Krems, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zsombor","family":"Lacza","sequence":"additional","affiliation":[{"name":"OrthoSera GmbH, 3500 Krems, Austria"},{"name":"Institute of Sport and Health Sciences, University of Physical Education, 1123 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Nehrer","sequence":"additional","affiliation":[{"name":"Center for Regenerative Medicine, Danube University Krems, 3500 Krems, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"De Luna","sequence":"additional","affiliation":[{"name":"Center for Regenerative Medicine, Danube University Krems, 3500 Krems, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"116861","DOI":"10.1016\/j.lfs.2019.116861","article-title":"The potential of exosomes in the therapy of the cartilage and bone complications; emphasis on osteoarthritis","volume":"236","author":"Pourakbari","year":"2019","journal-title":"Life Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1007\/s12178-011-9088-5","article-title":"Risk factors for incident osteoarthritis of the hip and knee","volume":"4","author":"Chaganti","year":"2011","journal-title":"Curr. Rev. Musculoskelet. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1659","DOI":"10.1136\/annrheumdis-2013-203355","article-title":"Incidence and risk factors for clinically diagnosed knee, hip and hand osteoarthritis: Influences of age, gender and osteoarthritis affecting other joints","volume":"73","author":"Judge","year":"2014","journal-title":"Ann. Rheum. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2428915","DOI":"10.1155\/2016\/2428915","article-title":"Extracellular Vesicles and Autophagy in Osteoarthritis","volume":"2016","author":"Gao","year":"2016","journal-title":"BioMed. Res. Int."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2870","DOI":"10.1073\/pnas.90.7.2870","article-title":"Osteoarthritis associated with mild chondrodysplasia in transgenic mice expressing alpha 1(IX) collagen chains with a central deletion","volume":"90","author":"Nakata","year":"1993","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1186\/ar148","article-title":"Articular cartilage and changes in arthritis. An introduction: Cell biology of osteoarthritis.","volume":"3","author":"Sandell","year":"2001","journal-title":"Arthritis Res."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Belluzzi, E., Macchi, V., Fontanella, C.G., Carniel, E.L., Olivotto, E., Filardo, G., Sarasin, G., Porzionato, A., Granzotto, M., and Pozzuoli, A. (2020). Infrapatellar Fat Pad Gene Expression and Protein Production in Patients with and without Osteoarthritis. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21176016"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1262","DOI":"10.1016\/j.knee.2017.08.001","article-title":"Age-related changes in the knee meniscus","volume":"24","author":"Tsujii","year":"2017","journal-title":"Knee"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Kardos, D., Marschall, B., Simon, M., Horny\u00e1k, I., Hinsenkamp, A., Kuten, O., Gyevn\u00e1r, Z., Erd\u00e9lyi, G., B\u00e1rdos, T., and Paukovits, T.M. (2019). Investigation of Cytokine Changes in Osteoarthritic Knee Joint Tissues in Response to Hyperacute Serum Treatment. Cells, 8.","DOI":"10.3390\/cells8080824"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1002\/art.27290","article-title":"The role of synovial macrophages and macrophage-produced mediators in driving inflammatory and destructive responses in osteoarthritis","volume":"62","author":"Bondeson","year":"2010","journal-title":"Arthritis Rheum."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/j.cyto.2005.04.009","article-title":"Gene expression profiling of serum- and interleukin-1 beta-stimulated primary human adult articular chondrocytes\u2014A molecular analysis based on chondrocytes isolated from one donor","volume":"31","author":"Aigner","year":"2005","journal-title":"Cytokine"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"499","DOI":"10.4049\/jimmunol.144.2.499","article-title":"IL-6 production by human articular chondrocytes. Modulation of its synthesis by cytokines, growth factors, and hormones in vitro","volume":"144","author":"Guerne","year":"1990","journal-title":"J. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"466","DOI":"10.4049\/jimmunol.148.2.466","article-title":"Cartilage and joint inflammation. Regulation of IL-8 expression by human articular chondrocytes","volume":"148","author":"Lotz","year":"1992","journal-title":"J. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3507","DOI":"10.1002\/jcb.23298","article-title":"ADAMTS-4 and ADAMTS-5: Key enzymes in osteoarthritis","volume":"112","author":"Verma","year":"2011","journal-title":"J. Cell Biochem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1016\/0167-4889(90)90145-4","article-title":"Modulation by interleukin 1 and tumor necrosis factor alpha of production of collagenase, tissue inhibitor of metalloproteinases and collagen types in differentiated and dedifferentiated articular chondrocytes","volume":"1052","author":"Lefebvre","year":"1990","journal-title":"Biochim. Biophys. Acta Moll. Cell Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1755","DOI":"10.3892\/mmr.2013.1729","article-title":"Tumor necrosis factor-alpha induces ADAMTS-4 expression in human osteoarthritis chondrocytes","volume":"8","author":"Xue","year":"2013","journal-title":"Mol. Med. Rep."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1002\/acr.24131","article-title":"2019 American College of Rheumatology\/Arthritis Foundation Guideline for the Management of Osteoarthritis of the Hand, Hip, and Knee","volume":"72","author":"Kolasinski","year":"2020","journal-title":"Arthritis Care Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1097\/BOR.0b013e32835aa28d","article-title":"Stem cell-based therapies for osteoarthritis: Challenges and opportunities","volume":"25","author":"Diekman","year":"2013","journal-title":"Curr. Opin. Rheumatol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1007\/s11420-017-9558-4","article-title":"Total Knee Arthroplasty for Knee Osteoarthritis: Support for a Foregone Conclusion?","volume":"13","author":"Steinhaus","year":"2017","journal-title":"HSS J.\u00ae"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1136\/ard.16.4.494","article-title":"Radiological Assessment of Osteo-Arthrosis","volume":"16","author":"Kellgren","year":"1957","journal-title":"Ann. Rheum. Dis."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Primorac, D., Molnar, V., Mati\u0161i\u0107, V., Hudetz, D., Jele\u010d, \u017d, Rod., E., \u010cukelj, F., Vidovi\u0107, D., Vrdoljak, T., and Dobri\u010dik, B. (2021). Comprehensive Review of Knee Osteoarthritis Pharmacological Treatment and the Latest Professional Societies\u2019 Guidelines. Pharmaceuticals, 14.","DOI":"10.3390\/ph14030205"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Neyret, P., Butcher, C., and Demey, G. (2020). Surgical Indications in the Treatment of Osteoarthritis. Surgery of the Knee, Springer International Publishing.","DOI":"10.1007\/978-3-030-19073-6"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1016\/j.biopha.2018.05.019","article-title":"Platelet rich plasma, stromal vascular fraction and autologous conditioned serum in treatment of knee osteoarthritis","volume":"104","author":"Fotouhi","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1007\/s12178-018-9527-7","article-title":"Current Clinical Recommendations for Use of Platelet-Rich Plasma","volume":"11","author":"Le","year":"2018","journal-title":"Curr. Rev. Musculoskelet. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1186\/scrt218","article-title":"Platelet-rich plasma preparation for regenerative medicine: Optimization and quantification of cytokines and growth factors","volume":"4","author":"Amable","year":"2013","journal-title":"Stem Cell Res. Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1007\/s12663-011-0182-4","article-title":"Platelet concentrates: Past, present and future","volume":"10","author":"Prakash","year":"2011","journal-title":"J. Maxillofac. Oral Surg."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/s40729-016-0052-4","article-title":"Growth factor and pro-inflammatory cytokine contents in platelet-rich plasma (PRP), plasma rich in growth factors (PRGF), advanced platelet-rich fibrin (A-PRF), and concentrated growth factors (CGF)","volume":"2","author":"Masuki","year":"2016","journal-title":"Int. J. Implant. Dent."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1902\/jop.2007.060302","article-title":"Platelet-rich plasma: Growth factors and pro-and anti-inflammatory properties","volume":"78","author":"Kantarci","year":"2007","journal-title":"J. Periodontol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1016\/j.arthro.2011.10.018","article-title":"Platelet-rich plasma: A milieu of bioactive factors","volume":"28","author":"Boswell","year":"2012","journal-title":"J. Arthrosc. Relat. Surg."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1272","DOI":"10.1016\/j.joca.2006.05.008","article-title":"Platelet-rich plasma stimulates porcine articular chondrocyte proliferation and matrix biosynthesis","volume":"14","author":"Akeda","year":"2006","journal-title":"Osteoarthr. Cartil."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1476","DOI":"10.1089\/ten.tea.2012.0225","article-title":"Dual effect of platelet lysate on human articular cartilage: A maintenance of chondrogenic potential and a transient proinflammatory activity followed by an inflammation resolution","volume":"19","author":"Pereira","year":"2013","journal-title":"Tissue Eng. Part A"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2135","DOI":"10.1177\/0363546511417792","article-title":"Growth factor and catabolic cytokine concentrations are influenced by the cellular composition of platelet-rich plasma","volume":"39","author":"Sundman","year":"2011","journal-title":"Am. J. Sports Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"5847","DOI":"10.1016\/j.biomaterials.2011.05.002","article-title":"Regenerative potentials of platelet-rich plasma enhanced by collagen in retrieving pro-inflammatory cytokine-inhibited chondrogenesis","volume":"32","author":"Wu","year":"2011","journal-title":"Biomaterials"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Filardo, G., Previtali, D., Napoli, F., Candrian, C., Zaffagnini, S., and Grassi, A. (2020). PRP Injections for the Treatment of Knee Osteoarthritis: A Meta-Analysis of Randomized Controlled Trials. Cartilage, 194760352093117.","DOI":"10.1177\/1947603520931170"},{"key":"ref_35","first-page":"2040622319825567","article-title":"Platelet-rich plasma in osteoarthritis treatment: Review of current evidence","volume":"10","author":"Blanco","year":"2019","journal-title":"Ther. Adv. Chronic Dis."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1177\/0363546517746112","article-title":"Concentrations of Blood Components in Commercial Platelet-Rich Plasma Separation Systems: A Review of the Literature","volume":"47","author":"Oudelaar","year":"2019","journal-title":"Am. J. Sports Med."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Kardos, D., Simon, M., V\u00e1cz, G., Hinsenkamp, A., Holczer, T., Cseh, D., S\u00e1rk\u00f6zi, A., Szenthe, K., B\u00e1n\u00e1ti, F., and Szathmary, S. (2019). The Composition of Hyperacute Serum and Platelet-Rich Plasma Is Markedly Different despite the Similar Production Method. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20030721"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.blre.2014.10.003","article-title":"Platelet secretion: From haemostasis to wound healing and beyond","volume":"29","author":"Golebiewska","year":"2015","journal-title":"Blood Rev."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1146\/annurev-cellbio-101512-122326","article-title":"Biogenesis, Secretion, and Intercellular Interactions of Exosomes and Other Extracellular Vesicles","volume":"30","author":"Colombo","year":"2014","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"27066","DOI":"10.3402\/jev.v4.27066","article-title":"Biological properties of extracellular vesicles and their physiological functions","volume":"4","author":"Siljander","year":"2015","journal-title":"J. Extracell. Vesicles"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1016\/j.jpedsurg.2017.01.032","article-title":"Breast milk-derived exosomes promote intestinal epithelial cell growth","volume":"52","author":"Hock","year":"2017","journal-title":"J. Pediatr. Surg."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"998","DOI":"10.1096\/fj.201600984R","article-title":"Saliva exosomes from pancreatic tumor-bearing mice modulate NK cell phenotype and antitumor cytotoxicity","volume":"31","author":"Katsiougiannis","year":"2017","journal-title":"FASEB J."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1089\/ten.teb.2014.0300","article-title":"Emerging roles for extracellular vesicles in tissue engineering and regenerative medicine","volume":"21","author":"Lamichhane","year":"2015","journal-title":"Tissue Eng. Part B Rev."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1251","DOI":"10.1074\/jbc.M115.662171","article-title":"Exosomes from HIV-1-infected Cells Stimulate Production of Pro-inflammatory Cytokines through Trans-activating Response (TAR) RNA","volume":"291","author":"Sampey","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_45","first-page":"1","article-title":"Post-translational add-ons mark the path in exosomal protein sorting","volume":"75","author":"Delgado","year":"2017","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1535750","DOI":"10.1080\/20013078.2018.1535750","article-title":"Minimal information for studies of extracellular vesicles 2018 (MISEV2018): A position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines","volume":"7","author":"Witwer","year":"2018","journal-title":"J. Extracell. Vesicles"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Xue, Q., Yan, Y., Zhang, R., and Xiong, H. (2018). Regulation of iNOS on Immune Cells and Its Role in Diseases. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19123805"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3089","DOI":"10.1172\/JCI83404","article-title":"p21 mediates macrophage reprogramming through regulation of p50-p50 NF-\u03baB and IFN-\u03b2","volume":"126","author":"Rackov","year":"2016","journal-title":"J. Clin. Investig."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1089\/ten.tea.2016.0007","article-title":"A Three-Dimensional Chondrocyte-Macrophage Coculture System to Probe Inflammation in Experimental Osteoarthritis","volume":"23","author":"Samavedi","year":"2017","journal-title":"Tissue Eng. Part A"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"584050","DOI":"10.3389\/fbioe.2020.584050","article-title":"Characterization and Chondroprotective Effects of Extracellular Vesicles From Plasma-and Serum-Based Autologous Blood-Derived Products for Osteoarthritis Therapy","volume":"8","author":"Otahal","year":"2020","journal-title":"Front. Bioeng. Biotechnol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1038\/s41598-018-36500-2","article-title":"Identification of Chondrocyte Genes and Signaling Pathways in Response to Acute Joint Inflammation","volume":"9","author":"Lv","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"938","DOI":"10.2353\/ajpath.2007.061083","article-title":"Activation of interleukin-1 signaling cascades in normal and osteoarthritic articular cartilage","volume":"171","author":"Fan","year":"2007","journal-title":"Am. J. Pathol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1186\/ar331","article-title":"Early response genes induced in chondrocytes stimulated with the inflammatory cytokine interleukin-1beta","volume":"3","author":"Vincenti","year":"2001","journal-title":"Arthritis Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1016\/j.joca.2016.04.019","article-title":"Identification of synovial fluid microRNA signature in knee osteoarthritis: Differentiating early-and late-stage knee osteoarthritis","volume":"24","author":"Li","year":"2016","journal-title":"Osteoarthr. Cartil."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1080\/19768354.2017.1406871","article-title":"Selective loading of exosomal HULC and miR-372 is responsible for chondrocyte death during OA pathogenesis","volume":"21","author":"Song","year":"2017","journal-title":"Anim. Cells Syst."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1038\/s41419-020-03127-z","article-title":"Macrophage-derived extracellular vesicles: Diverse mediators of pathology and therapeutics in multiple diseases","volume":"11","author":"Wang","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_57","first-page":"3","article-title":"Isolation and characterization of exosomes from cell culture supernatants and biological fluids","volume":"30","author":"Amigorena","year":"2006","journal-title":"Curr. Protoc. Cell. Biol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"585","DOI":"10.3109\/17453674.2013.854666","article-title":"Toll-like receptors in human chondrocytes and osteoarthritic cartilage","volume":"84","author":"Sillat","year":"2013","journal-title":"Acta Orthop."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1016\/j.joca.2020.01.011","article-title":"Role of TLR2 and TLR4 in regulation of articular chondrocyte homeostasis","volume":"28","author":"Wang","year":"2020","journal-title":"Osteoarthr. Cartil."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1880","DOI":"10.1002\/art.22637","article-title":"Toll-like receptors and chondrocytes: The lipopolysaccharide-induced decrease in cartilage matrix synthesis is dependent on the presence of toll-like receptor 4 and antagonized by bone morphogenetic protein 7","volume":"56","author":"Bobacz","year":"2007","journal-title":"Arthritis Rheum."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1560809","DOI":"10.1080\/20013078.2018.1560809","article-title":"Comparison of small extracellular vesicles isolated from plasma by ultracentrifugation or size-exclusion chromatography: Yield, purity and functional potential","volume":"8","author":"Takov","year":"2019","journal-title":"J. Extracell. Vesicles"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"2873","DOI":"10.1007\/s00018-018-2773-4","article-title":"Detailed analysis of the plasma extracellular vesicle proteome after separation from lipoproteins","volume":"75","author":"Karimi","year":"2018","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Palviainen, M., Saraswat, M., Varga, Z., Kitka, D., Neuvonen, M., Puhka, M., Joenv\u00e4\u00e4r\u00e4, S., Renkonen, R., Nieuwland, R., and Takatalo, M. (2020). Extracellular vesicles from human plasma and serum are carriers of extravesicular cargo-Implications for biomarker discovery. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0236439"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"3451","DOI":"10.1038\/s41598-017-03759-w","article-title":"IL-6 secretion in osteoarthritis patients is mediated by chondrocyte-synovial fibroblast cross-talk and is enhanced by obesity","volume":"7","author":"Pearson","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1002\/jcb.20466","article-title":"Wnt-mediated regulation of chondrocyte maturation: Modulation by TGF-beta","volume":"95","author":"Dong","year":"2005","journal-title":"J. Cell. Biochem."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/j.gendis.2015.09.003","article-title":"Multifaceted signaling regulators of chondrogenesis: Implications in cartilage regeneration and tissue engineering","volume":"2","author":"Green","year":"2015","journal-title":"Genes Dis."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1089\/ten.tea.2017.0384","article-title":"The Effects of Hyperacute Serum on Adipogenesis and Cell Proliferation of Mesenchymal Stromal Cells","volume":"24","author":"Kuten","year":"2018","journal-title":"Tissue Eng. Part A"},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"EV-TRACK Consortium, Van Deun, J., Mestdagh, P., Agostinis, P., Akay, \u00d6., Anand, S., Anckaert, J., Martinez, Z.A., Baetens, T., and Beghein, E. (2017). EV-TRACK: Transparent reporting and centralizing knowledge in extracellular vesicle research. Nat. Methods, 14, 228\u2013232.","DOI":"10.1038\/nmeth.4185"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"19671","DOI":"10.3402\/jev.v2i0.19671","article-title":"Extracellular vesicle sizing and enumeration by nanoparticle tracking analysis","volume":"2","author":"Gardiner","year":"2013","journal-title":"J. Extracell. Vesicles"},{"key":"ref_70","first-page":"e50974","article-title":"An innovative method for exosome quantification and size measurement","volume":"2015","author":"Mehdiani","year":"2015","journal-title":"J. Vis. Exp."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"5823","DOI":"10.1038\/s41598-021-84234-5","article-title":"Functional repertoire of EV-associated miRNA profiles after lipoprotein depletion via ultracentrifugation and size exclusion chromatography from autologous blood products","volume":"11","author":"Otahal","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"De Luna-Preitschopf, A., Zwickl, H., Nehrer, S., Hengstschl\u00e4ger, M., and Mikula, M. (2017). Rapamycin Maintains the Chondrocytic Phenotype and Interferes with Inflammatory Cytokine Induced Processes. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18071494"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1186\/s12950-016-0139-y","article-title":"Chondroprotective effect of high-molecular-weight hyaluronic acid on osteoarthritic chondrocytes in a co-cultivation inflammation model with M1 macrophages","volume":"13","author":"Bauer","year":"2016","journal-title":"J. Inflamm."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1093\/biomet\/93.3.491","article-title":"Adaptive linear step-up procedures that control the false discovery rate","volume":"93","author":"Benjamini","year":"2006","journal-title":"Biometrika"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/13\/7224\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:26:16Z","timestamp":1760163976000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/13\/7224"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,5]]},"references-count":74,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2021,7]]}},"alternative-id":["ijms22137224"],"URL":"https:\/\/doi.org\/10.3390\/ijms22137224","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,5]]}}}