{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T13:16:17Z","timestamp":1788441377362,"version":"build-2803163510"},"reference-count":48,"publisher":"IMR Press","issue":"8","license":[{"start":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T00:00:00Z","timestamp":1786665600000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Union\u2014Next Generation EU\u2014NRRP M6C2\u2014Investment 2.1 Enhancement and strengthening of biomedical research in the NHS\u2014Project","award":["PNRR-MCNT2-2023-12377836"],"award-info":[{"award-number":["PNRR-MCNT2-2023-12377836"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Front. Biosci. (Landmark Ed)"],"abstract":"<jats:p>Background:The limited intrinsic repair capacity of articular cartilage impairs tissue regeneration in osteoarthritis (OA). Platelet-rich plasma (PRP) fibrin gels offer a viable autologous scaffold for cartilage repair but often promote fibrous tissue rather than native hyaline structures. Mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) can overcome this limitation by actively promoting hyaline cartilage formation and suppressing matrix degradation. This study describes and validates a protocol for embedding adipose-derived MSC (ASC)-EVs into PRP gels (PRP-EVs) and evaluates the protective efficacy in human pathologic chondrocytes and synoviocytes.Methods:ASC-EVs were isolated via ultracentrifugation, characterized and their microRNA cargo profiled (quantitative reverse-transcription polymerase chain reaction, qRT-PCR). EVs (10 \u00d7 109 particles\/mL) were loaded into PRP activated with CaCl2 to form a fibrin hydrogel. EV incorporation efficiency, 4-week release kinetics, cellular uptake (two-dimensional [2D] and three-dimensional [3D] microfluidic models) and penetration into OA cartilage explants using coherent anti-Stokes Raman scattering\/two-photon excited fluorescence CARS\/TPEF microscopy were assessed. To evaluate the biological effects of the PRP-EV gel secretome, we analyzed gene expression (qRT-PCR), collagen I\/II\/X deposition (immunofluorescence), metalloproteinase activity and nitric oxide release (ELISA) in interleukin-1\u03b2-stimulated 3D chondrocyte pellets, alongside gene expression in OA patient-derived synoviocytes (qRT-PCR).Results:The protocol demonstrated high EV encapsulation efficiency (60% \u00b1 8 of the input) in PRP gels and steady kinetics yielding a 20% cumulative release over 4 weeks. Released EVs maintained functional integrity, showing matching 2D\/3D uptake in target cells and penetrating to depths exceeding 200 \u03bcm within 48 hoursinto OA patients\u2019 cartilage explants. In 3D chondrocyte pellets, PRP-EVs significantly downregulated catabolic genes (MMP1, MMP3, MMP13), reducing cumulative matrix metalloproteinase (MMP) enzymatic activity, and blunted nitric oxide production and CCL5 expression. PRP-EVs counteracted PRP-induced fibrosis, significantly increasing the collagen II\/I ratio and suppressing hypertrophic collagen X deposition. In synoviocytes, PRP-EVs significantly downregulated key inflammatory, chemotactic, and pain-signaling genes (CCL2, CXCL8, CXCL10, IL-6, COX2, NGF).Conclusions:This study demonstrates that embedding ASC-EVs within a PRP fibrin hydrogel creates a bioactive delivery system. In vitro, the secretome released from this composite material successfully counteracts pathological processes in osteoarthritis patient-derived chondrocytes and synoviocytes, reducing matrix degradation and inflammation while promoting a hyaline-like cartilage phenotype.<\/jats:p>","DOI":"10.31083\/fbl54998","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T12:35:31Z","timestamp":1788438931000},"source":"Crossref","is-referenced-by-count":0,"title":["Matrix Protective and Anti-Inflammatory In Vitro Potential of Adipose Mesenchymal Stromal Cell-Derived EVs Coupled With Platelet-Derived Fibrin Gel"],"prefix":"10.31083","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0272-7417","authenticated-orcid":true,"given":"Enrico","family":"Ragni","sequence":"first","affiliation":[{"name":"Laboratorio di Biotecnologie Applicate all\u2019Ortopedia, IRCCS Ospedale Galeazzi-Sant\u2019Ambrogio, 20157 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8257-8831","authenticated-orcid":true,"given":"Michela","family":"Taiana","sequence":"additional","affiliation":[{"name":"Laboratorio di Biotecnologie Applicate all\u2019Ortopedia, IRCCS Ospedale Galeazzi-Sant\u2019Ambrogio, 20157 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6688-4492","authenticated-orcid":true,"given":"Simona","family":"Landoni","sequence":"additional","affiliation":[{"name":"Laboratorio di Biotecnologie Applicate all\u2019Ortopedia, IRCCS Ospedale Galeazzi-Sant\u2019Ambrogio, 20157 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4468-7628","authenticated-orcid":true,"given":"Federico","family":"Valli","sequence":"additional","affiliation":[{"name":"Department of Chirurgia Articolare Sostitutiva e Chirurgia Ortopedica, IRCCS Ospedale Galeazzi-Sant\u2019Ambrogio, 20157 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-3166-8736","authenticated-orcid":true,"given":"Andrea Massimiliano","family":"Nebuloni","sequence":"additional","affiliation":[{"name":"Laboratorio di Biotecnologie Applicate all\u2019Ortopedia, IRCCS Ospedale Galeazzi-Sant\u2019Ambrogio, 20157 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9810-8818","authenticated-orcid":true,"given":"Paola","family":"De Luca","sequence":"additional","affiliation":[{"name":"Laboratorio di Biotecnologie Applicate all\u2019Ortopedia, IRCCS Ospedale Galeazzi-Sant\u2019Ambrogio, 20157 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9434-4538","authenticated-orcid":true,"given":"Lorenza","family":"Lazzari","sequence":"additional","affiliation":[{"name":"Unit of Cell and Gene Therapies, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9979-3092","authenticated-orcid":true,"given":"Laura","family":"de Girolamo","sequence":"additional","affiliation":[{"name":"Laboratorio di Biotecnologie Applicate all\u2019Ortopedia, IRCCS Ospedale Galeazzi-Sant\u2019Ambrogio, 20157 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9341-7187","authenticated-orcid":true,"given":"Giuseppe","family":"Peretti","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences for Health, University of Milan, 20133 Milan, Italy"},{"name":"\u00c9quipe Universitaria di Ortopedia Rigenerativa e Ricostruttiva, IRCCS Ospedale Galeazzi-Sant\u2019Ambrogio, 20157 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2026,8,14]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Oliveira S, Hinckel BB, Silva FS, Carvalho \u00d3, Leal A. A guide to articular cartilage functioning: a comprehensive review, current challenges and mechanobiological solutions. Progress in Biomedical Engineering (Bristol, England). 2025; 7:  https:\/\/doi.org\/10.1088\/2516-1091\/ade83a","DOI":"10.1088\/2516\u20131091\/ade83a"},{"key":"ref2","doi-asserted-by":"publisher","unstructured":"Sanchez-Lopez E, Coras R, Torres A, Lane NE, Guma M. Synovial inflammation in osteoarthritis progression. Nature Reviews. Rheumatology. 2022; 18: 258\u2013275.","DOI":"10.1038\/s41584-022-00749-9"},{"key":"ref3","doi-asserted-by":"publisher","unstructured":"Delattre BMA, Hilbert T, Kutaish H, Crowe LA, Poletti PA, Menetrey J, et al. Healthy knee cartilage T2 mapping assessed with GRAPPATINI and multi-echo spin-echo (MESE) at 3T: regional values, longitudinal repeatability and method agreement. Quantitative Imaging in Medicine and Surgery. 2026; 16: 337.","DOI":"10.21037\/qims-2025-1-2462"},{"key":"ref4","doi-asserted-by":"publisher","unstructured":"GBD 2021 Osteoarthritis Collaborators. Global, regional, and national burden of osteoarthritis, 1990-2020 and projections to 2050: a systematic analysis for the Global Burden of Disease Study 2021. The Lancet. Rheumatology. 2023; 5: e508\u2013e522.","DOI":"10.1016\/S2665-9913(23)00163-7"},{"key":"ref5","doi-asserted-by":"publisher","unstructured":"Garc\u00eda JR, Acu\u00f1a AJ, Villareal JB, Saad Berreta R, Gonzalez Ayala S, del Ba\u00f1o-Barrag\u00e1n L, et al. New horizons in cartilage repair: update on treatment trends and outcomes. Journal of Cartilage & Joint Preservation. 2024; 2: 100179.","DOI":"10.1016\/j.jcjp.2024.100179"},{"key":"ref6","doi-asserted-by":"publisher","unstructured":"Caplan AI. Mesenchymal Stem Cells: Time to Change the Name! Stem Cells Translational Medicine. 2017; 6: 1445\u20131451.","DOI":"10.1002\/sctm.17-0051"},{"key":"ref7","doi-asserted-by":"publisher","unstructured":"Wei W, Ao Q, Wang X, Cao Y, Liu Y, Zheng SG, et al. Mesenchymal Stem Cell-Derived Exosomes: A Promising Biological Tool in Nanomedicine. Frontiers in Pharmacology. 2021; 11: 590470.","DOI":"10.3389\/fphar.2020.590470"},{"key":"ref8","doi-asserted-by":"publisher","unstructured":"Torres-Torrillas M, Rubio M, Damia E, Cuervo B, Del Romero A, Pel\u00e1ez P, et al. Adipose-Derived Mesenchymal Stem Cells: A Promising Tool in the Treatment of Musculoskeletal Diseases. International Journal of Molecular Sciences. 2019; 20: 3105.","DOI":"10.3390\/ijms20123105"},{"key":"ref9","doi-asserted-by":"publisher","unstructured":"Ragni E, Perucca Orfei C, Sinigaglia F, de Girolamo L. Joint Tissue Protective and Immune-Modulating miRNA Landscape of Mesenchymal Stromal Cell-Derived Extracellular Vesicles under Different Osteoarthritis-Mimicking Conditions. Pharmaceutics. 2022; 14: 1400.","DOI":"10.3390\/pharmaceutics14071400"},{"key":"ref10","doi-asserted-by":"publisher","unstructured":"Ragni E, Colombini A, Vigan\u00f2 M, Libonati F, Perucca Orfei C, Zagra L, et al. Cartilage Protective and Immunomodulatory Features of Osteoarthritis Synovial Fluid-Treated Adipose-Derived Mesenchymal Stem Cells Secreted Factors and Extracellular Vesicles-Embedded miRNAs. Cells. 2021; 10: 1072.","DOI":"10.3390\/cells10051072"},{"key":"ref11","doi-asserted-by":"publisher","unstructured":"Ragni E, Perucca Orfei C, De Luca P, Mondadori C, Vigan\u00f2 M, Colombini A, et al. Inflammatory priming enhances mesenchymal stromal cell secretome potential as a clinical product for regenerative medicine approaches through secreted factors and EV-miRNAs: the example of joint disease. Stem Cell Research & Therapy. 2020; 11: 165.","DOI":"10.1186\/s13287-020-01677-9"},{"key":"ref12","doi-asserted-by":"publisher","unstructured":"Kang J, Jie L, Fu H, Zhang L, Lu G, Yu L, et al. Adipose Mesenchymal Stem Cells Derived Exosomes Ameliorates KOA Cartilage Damage and Inflammation by Activation of PINK1-Mediated Mitochondrial Autophagy. FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology. 2025; 39: e70811.","DOI":"10.1096\/fj.202501185R"},{"key":"ref13","doi-asserted-by":"publisher","unstructured":"Chen KT, Huang CC, Yadav VK, Pikatan NW, Fong IH, Kuo KT, et al. Gluteal adipose-derived stem cell exosomes promote macrophage polarization and cartilage regeneration in osteoarthritis via PTPRC modulation. Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie. 2026; 196: 119130.","DOI":"10.1016\/j.biopha.2026.119130"},{"key":"ref14","doi-asserted-by":"publisher","unstructured":"Akbar A, Dilogo IH, Antarianto RD, Kousar I, Tantry AJ, Canintika AF. Intra-Articular Injection of Adipose-Derived-MSC Exosomes and Hyaluronic Acid in Sheep Knee Osteoarthritic Models Enhances Hyaline Cartilage Regeneration. Biomedicines. 2025; 13: 3070.","DOI":"10.3390\/biomedicines13123070"},{"key":"ref15","doi-asserted-by":"publisher","unstructured":"Woo CH, Kim HK, Jung GY, Jung YJ, Lee KS, Yun YE, et al. Small extracellular vesicles from human adipose-derived stem cells attenuate cartilage degeneration. Journal of Extracellular Vesicles. 2020; 9: 1735249.","DOI":"10.1080\/20013078.2020.1735249"},{"key":"ref16","doi-asserted-by":"publisher","unstructured":"Fu YJ, Jian J, Liu C, Yi YF, Ding YT, Wen J, et al. Application of stem cell-derived exosomes in bone and joint diseases: Recent advances enabled by diverse carrier technologies. World Journal of Stem Cells. 2025; 17: 113631.","DOI":"10.4252\/wjsc.v17.i11.113631"},{"key":"ref17","doi-asserted-by":"publisher","unstructured":"Rahmati S, Khazaei M, Nadi A, Alizadeh M, Rezakhani L. Exosome-loaded scaffolds for regenerative medicine in hard tissues. Tissue & Cell. 2023; 82: 102102.","DOI":"10.1016\/j.tice.2023.102102"},{"key":"ref18","doi-asserted-by":"publisher","unstructured":"Su CY, Kuo YP, Nieh HL, Tseng YH, Burnouf T. Quantitative assessment of the kinetics of growth factors release from platelet gel. Transfusion. 2008; 48: 2414\u20132420.","DOI":"10.1111\/j.1537-2995.2008.01862.x"},{"key":"ref19","doi-asserted-by":"publisher","unstructured":"Jalowiec JM, D'Este M, Bara JJ, Denom J, Menzel U, Alini M, et al. An In Vitro Investigation of Platelet-Rich Plasma-Gel as a Cell and Growth Factor Delivery Vehicle for Tissue Engineering. Tissue Engineering. Part C, Methods. 2016; 22: 49\u201358.","DOI":"10.1089\/ten.TEC.2015.0223"},{"key":"ref20","doi-asserted-by":"publisher","unstructured":"Carneiro MDO, Barbieri CH, Barbieri Neto J. Platelet-rich plasma gel promotes regeneration of articular cartilage in knees of sheeps. Acta Ortopedica Brasileira. 2013; 21: 80\u201386.","DOI":"10.1590\/S1413-78522013000200003"},{"key":"ref21","unstructured":"Papalia R, Diaz Balzani L, Torre G, Tirindelli MC, Nobile C, Maffulli N, et al. Intraoperative application Platelet rich fibrin, postoperative injections OF PRP or microfracture only for osteochondral lesions of the knee: a five-year retrospective evaluation. Journal of Biological Regulators and Homeostatic Agents. 2016; 30: 41\u201349."},{"key":"ref22","doi-asserted-by":"publisher","unstructured":"Ragni E, De Luca P, Landoni S, Valli F, Mortati L, Palombella S, et al. High efficiency protocol for platelet derived fibrin gel loaded with mesenchymal stromal cells extracellular vesicles. Regenerative Therapy. 2024; 26: 442\u2013457.","DOI":"10.1016\/j.reth.2024.06.020"},{"key":"ref23","doi-asserted-by":"publisher","unstructured":"Taiana MM, Landoni S, Valli F, de Girolamo L, Ragni E, de Luca P. Extracellular vesicles outperform adipose derived-mesenchymal stromal cells in alleviating osteoarthritis chondrocyte inflammation in vitro when incorpo-rated into platelet-derived fibrin gel. Ligaments and Tendons Journal. 2026; 16.","DOI":"10.32098\/mltj_2026_6387"},{"key":"ref24","doi-asserted-by":"publisher","unstructured":"Chang L, Xia J. MicroRNA Regulatory Network Analysis Using miRNet 2.0. Methods in Molecular Biology (Clifton, N.J.). 2023; 2594: 185\u2013204.","DOI":"10.1007\/978-1-0716-2815-7_14"},{"key":"ref25","doi-asserted-by":"publisher","unstructured":"Metsalu T, Vilo J. ClustVis: a web tool for visualizing clustering of multivariate data using Principal Component Analysis and heatmap. Nucleic Acids Research. 2015; 43: W566\u201370.","DOI":"10.1093\/nar\/gkv468"},{"key":"ref26","doi-asserted-by":"publisher","unstructured":"Toh WS, Lai RC, Zhang B, Lim SK. MSC exosome works through a protein-based mechanism of action. Biochemical Society Transactions. 2018; 46: 843\u2013853.","DOI":"10.1042\/BST20180079"},{"key":"ref27","doi-asserted-by":"publisher","unstructured":"Chevillet JR, Kang Q, Ruf IK, Briggs HA, Vojtech LN, Hughes SM, et al. Quantitative and stoichiometric analysis of the microRNA content of exosomes. Proceedings of the National Academy of Sciences of the United States of America. 2014; 111: 14888\u201314893.","DOI":"10.1073\/pnas.1408301111"},{"key":"ref28","doi-asserted-by":"publisher","unstructured":"Endisha H, Rockel J, Jurisica I, Kapoor M. The complex landscape of microRNAs in articular cartilage: biology, pathology, and therapeutic targets. JCI Insight. 2018; 3: e121630.","DOI":"10.1172\/jci.insight.121630"},{"key":"ref29","doi-asserted-by":"publisher","unstructured":"Sun Y, You Y, Wu Q, Hu R, Dai K. Senescence-targeted MicroRNA\/Organoid composite hydrogel repair cartilage defect and prevention joint degeneration via improved chondrocyte homeostasis. Bioactive Materials. 2024; 39: 427\u2013442.","DOI":"10.1016\/j.bioactmat.2024.05.036"},{"key":"ref30","doi-asserted-by":"publisher","unstructured":"Xu J, Qian X, Ding R. MiR-24-3p attenuates IL-1\u03b2-induced chondrocyte injury associated with osteoarthritis by targeting BCL2L12. Journal of Orthopaedic Surgery and Research. 2021; 16: 371.","DOI":"10.1186\/s13018-021-02378-6"},{"key":"ref31","doi-asserted-by":"publisher","unstructured":"Philipot D, Gu\u00e9rit D, Platano D, Chuchana P, Olivotto E, Espinoza F, et al. p16INK4a and its regulator miR-24 link senescence and chondrocyte terminal differentiation-associated matrix remodeling in osteoarthritis. Arthritis Research & Therapy. 2014; 16: R58.","DOI":"10.1186\/ar4494"},{"key":"ref32","doi-asserted-by":"publisher","unstructured":"Liu X, Feng F, Jin Y, Ma C, Zhu Q, You Y, et al. Loss of the miR-221\/222 Cluster Promotes the Pathogenesis of Osteoarthritis in Inflamed Mouse Chondrocytes and Osteoarthritis Models. Inflammation. 2025; 49: 2.","DOI":"10.1007\/s10753-025-02411-4"},{"key":"ref33","doi-asserted-by":"publisher","unstructured":"Song J, Jin EH, Kim D, Kim KY, Chun CH, Jin EJ. MicroRNA-222 regulates MMP-13 via targeting HDAC-4 during osteoarthritis pathogenesis. BBA Clinical. 2014; 3: 79\u201389.","DOI":"10.1016\/j.bbacli.2014.11.009"},{"key":"ref34","doi-asserted-by":"publisher","unstructured":"Meng F, Li Z, Zhang Z, Yang Z, Kang Y, Zhao X, et al. MicroRNA-193b-3p regulates chondrogenesis and chondrocyte metabolism by targeting HDAC3. Theranostics. 2018; 8: 2862\u20132883.","DOI":"10.7150\/thno.23547"},{"key":"ref35","doi-asserted-by":"publisher","unstructured":"Chen X, Zhang R, Zhang Q, Xu Z, Xu F, Li D, et al. Chondrocyte sheet in vivo cartilage regeneration technique using miR-193b-3p to target MMP16. Aging. 2019; 11: 7070\u20137082.","DOI":"10.18632\/aging.102237"},{"key":"ref36","doi-asserted-by":"publisher","unstructured":"Kouroupis D, Kaplan LD, Best TM. Human infrapatellar fat pad mesenchymal stem cells show immunomodulatory exosomal signatures. Scientific Reports. 2022; 12: 3609.","DOI":"10.1038\/s41598-022-07569-7"},{"key":"ref37","doi-asserted-by":"publisher","unstructured":"Mukherjee A, Das B. The role of inflammatory mediators and matrix metalloproteinases (MMPs) in the progression of osteoarthritis. Biomaterials and Biosystems. 2024; 13: 100090.","DOI":"10.1016\/j.bbiosy.2024.100090"},{"key":"ref38","doi-asserted-by":"publisher","unstructured":"Rediske JJ, Koehne CF, Zhang B, Lotz M. The inducible production of nitric oxide by articular cell types. Osteoarthritis and Cartilage. 1994; 2: 199\u2013206.","DOI":"10.1016\/s1063-4584(05)80069-x"},{"key":"ref39","doi-asserted-by":"publisher","unstructured":"Costa RM, Cerqueira DM, Bruder-Nascimento A, Alves JV, Awata WMC, Singh S, et al. Role of the CCL5 and Its Receptor, CCR5, in the Genesis of Aldosterone-Induced Hypertension, Vascular Dysfunction, and End-Organ Damage. Hypertension (Dallas, Tex. : 1979). 2024; 81: 776\u2013786.","DOI":"10.1161\/HYPERTENSIONAHA.123.21888"},{"key":"ref40","doi-asserted-by":"publisher","unstructured":"Choi MC, Jo J, Park J, Kang HK, Park Y. NF-\u03baB Signaling Pathways in Osteoarthritic Cartilage Destruction. Cells. 2019; 8: 734.","DOI":"10.3390\/cells8070734"},{"key":"ref41","doi-asserted-by":"publisher","unstructured":"Dreier R. Hypertrophic differentiation of chondrocytes in osteoarthritis: the developmental aspect of degenerative joint disorders. Arthritis Research & Therapy. 2010; 12: 216.","DOI":"10.1186\/ar3117"},{"key":"ref42","doi-asserted-by":"publisher","unstructured":"To K, Romain K, Mak C, Kamaraj A, Henson F, Khan W. The Treatment of Cartilage Damage Using Human Mesenchymal Stem Cell-Derived Extracellular Vesicles: A Systematic Review of in vivo Studies. Frontiers in Bioengineering and Biotechnology. 2020; 8: 580.","DOI":"10.3389\/fbioe.2020.00580"},{"key":"ref43","doi-asserted-by":"publisher","unstructured":"Thielen NGM, van der Kraan PM, van Caam APM. TGF\u03b2\/BMP Signaling Pathway in Cartilage Homeostasis. Cells. 2019; 8: 969.","DOI":"10.3390\/cells8090969"},{"key":"ref44","doi-asserted-by":"publisher","unstructured":"Mobasheri A, Castro-Dom\u00ednguez F, Gualillo O, Kluzek S, Ruiz SP, Largo R. Targeting synovial inflammation in knee osteoarthritis: translational insights for diagnosis and therapy. Journal of Orthopaedic Translation. 2026; 56: 101012.","DOI":"10.1016\/j.jot.2025.10.004"},{"key":"ref45","doi-asserted-by":"publisher","unstructured":"Zhang S, Teo KYW, Chuah SJ, Lai RC, Lim SK, Toh WS. MSC exosomes alleviate temporomandibular joint osteoarthritis by attenuating inflammation and restoring matrix homeostasis. Biomaterials. 2019; 200: 35\u201347.","DOI":"10.1016\/j.biomaterials.2019.02.006"},{"key":"ref46","doi-asserted-by":"publisher","unstructured":"Khatab S, van Osch GJ, Kops N, Bastiaansen-Jenniskens YM, Bos PK, Verhaar JA, et al. Mesenchymal stem cell secretome reduces pain and prevents cartilage damage in a murine osteoarthritis model. European Cells & Materials. 2018; 36: 218\u2013230.","DOI":"10.22203\/eCM.v036a16"},{"key":"ref47","doi-asserted-by":"publisher","unstructured":"Obeidat AM, Newton MD, Li J, Hu B, Ishihara S, Lammlin L, et al. Nerve Growth Factor is Sufficient to Cause Multiple Osteoarthritis-Relevant Pathologic Features in Na\u00efve Murine Knee Joints. Arthritis & Rheumatology (Hoboken, N.J.). 2026;  https:\/\/doi.org\/10.1002\/art.70168","DOI":"10.1002\/art.70168"},{"key":"ref48","doi-asserted-by":"publisher","unstructured":"Crofford LJ. COX-2 in synovial tissues. Osteoarthritis and Cartilage. 1999; 7: 406\u2013408.","DOI":"10.1053\/joca.1999.0226"}],"container-title":["Frontiers in Bioscience-Landmark"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.imrpress.com\/journal\/FBL\/31\/8\/10.31083\/FBL54998","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T12:36:27Z","timestamp":1788438987000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.imrpress.com\/journal\/FBL\/31\/8\/10.31083\/FBL54998"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,14]]},"references-count":48,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2026]]}},"alternative-id":["S2768-6701(26)02231-8"],"URL":"https:\/\/doi.org\/10.31083\/fbl54998","relation":{},"ISSN":["2768-6701","2768-6698"],"issn-type":[{"value":"2768-6701","type":"print"},{"value":"2768-6698","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,14]]},"article-number":"54998"}}