{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T23:44:58Z","timestamp":1790639098772,"version":"4.1.0"},"reference-count":107,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,5,26]],"date-time":"2025-05-26T00:00:00Z","timestamp":1748217600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      Arthritis, a disease affecting over 50 million adults in the United States, encompasses many different conditions involving joints and surrounding tissues. Disease development, progression, and subsequent treatment is dependent on many different factors, including the relationship between adjacent tissues and the immunological signals involved. A major contributor to disease regulation is the crosstalk between the cartilage and the bone in joints, as well as their reaction to immune factors such as cytokine signaling and macrophage mediation. Studying cartilage-bone crosstalk in arthritis development can be difficult, as controlling immunological factors\n                      <jats:italic>in vivo<\/jats:italic>\n                      is challenging, but\n                      <jats:italic>in vitro<\/jats:italic>\n                      models often lack multi-tissue relevancy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      To fix this, we developed an\n                      <jats:italic>in vitro<\/jats:italic>\n                      micro-physiological system using a biphasic bioreactor that supports modeling of multiple tissues. We generated cartilage and vascularized-bone analogs and combined them in the bioreactor to allow diffusion and signaling between them. Using this system, we directly induced inflammation in the cartilage region and studied how crosstalk between the two adjacent tissues contributed to disease progression.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We showed that conditioned media from pro-inflammatory macrophages generated a different inflammatory profile than a simple inflammatory cytokine cocktail. We also showed that the vascularized-bone region became inflamed in response to the cartilage inflammation, verifying crosstalk in the system and successfully modeling the relationship between cartilage and bone in an arthritic environment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>\n                      This model can be used to further probe the crosstalk between bone and cartilage in arthritis, allowing researchers to tease out the effect of specific inflammatory agents or therapeutics\n                      <jats:italic>in vitro<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1495613","type":"journal-article","created":{"date-parts":[[2025,5,26]],"date-time":"2025-05-26T01:17:55Z","timestamp":1748222275000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["Developing an in vitro osteochondral micro-physiological system for modeling cartilage-bone crosstalk in arthritis"],"prefix":"10.3389","volume":"16","author":[{"given":"Kyra W. Y.","family":"Smith","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie L.","family":"Fung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsin-Fang","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Chiesa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Vozzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmelo","family":"De Maria","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riccardo","family":"Gottardi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,5,26]]},"reference":[{"key":"B1","article-title":"Articular cartilage structure, composition, and function","author":"Mankin","year":"2000","journal-title":"Orthop basic Sci"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1007\/s10067-020-05054-y","article-title":"Rheumatoid arthritis and osteoarthritis clinical practice guidelines provide few complementary and alternative medicine therapy recommendations: a systematic review","volume":"39","author":"Ng","year":"2020","journal-title":"Clin Rheumatol"},{"key":"B3","unstructured":"Morbidity and mortality weekly report prevalence of diagnosed arthritis-United States 2019-2021\n          \n          \n            \n              Fallon\n              EA\n            \n            \n              Boring\n              MA\n            \n            \n              Foster\n              AL\n            \n            \n              Stowe\n              EW\n            \n            \n              Lites\n              TD\n            \n            \n              Odom\n              EL\n            \n          \n          \n          2019"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1080\/10717544.2022.2048130","article-title":"Intra-articular drug delivery systems for osteoarthritis therapy: shifting from sustained release to enhancing penetration into cartilage","volume":"29","author":"Huang","year":"2022","journal-title":"Drug Deliv"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.2147\/DDDT.S295224","article-title":"The development of disease-modifying therapies for osteoarthritis (DMOADs): the evidence to date","volume":"15","author":"Oo","year":"2021","journal-title":"Drug Des Devel. Ther"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1002\/bdrc.20050","article-title":"Mechanisms of synovial joint and articular cartilage formation: Recent advances, but many lingering mysteries","volume":"75","author":"Pacifici","year":"2005","journal-title":"Birth Defects Res Part C - Embryo Today Rev"},{"key":"B7","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1089\/ten.tec.2019.0116","article-title":"A systematic review and guide to mechanical testing for articular cartilage tissue engineering","volume":"25","author":"Patel","year":"2019","journal-title":"Tissue Eng. - Part C Methods"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1155\/2015\/421746","article-title":"Biology of bone tissue: structure, function, and factors that influence bone cells","volume":"2015","author":"Florencio-Silva","year":"2015","journal-title":"BioMed Res Int"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3389\/fvets.2018.00178","article-title":"The importance of subchondral bone in the pathophysiology of osteoarthritis","volume":"5","author":"Stewart","year":"2018","journal-title":"Front Vet Sci"},{"key":"B10","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41413-021-00147-z","article-title":"Subchondral bone microenvironment in osteoarthritis and pain","volume":"9","author":"Hu","year":"2021","journal-title":"Bone Res"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-030-99612-3","author":"Scanzello","year":"2022","journal-title":"Synovial fluid analysis and the evaluation of patients with arthritis"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1101\/2023.10.03.559514","article-title":"Synovial macrophage diversity and activation of M-CSF signaling in post-traumatic osteoarthritis","author":"Knights","year":"2023","journal-title":"bioRxiv Prepr. Serv. Biol"},{"key":"B13","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1007\/s10456-017-9541-1","article-title":"The role of vasculature in bone development, regeneration and proper systemic functioning","volume":"20","author":"Filipowska","year":"2017","journal-title":"Angiogenesis"},{"key":"B14","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1016\/j.jot.2013.11.004","article-title":"Importance of subchondral bone in the pathogenesis and management of osteoarthritis from bench to bed","volume":"2","author":"Wen","year":"2014","journal-title":"J Orthop Transl"},{"key":"B15","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/ar2292","article-title":"Cells of the synovium in rheumatoid arthritis. Chondrocytes","volume":"9","author":"Otero","year":"2007","journal-title":"Arthritis Res Ther"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2016.148","article-title":"Changes in the osteochondral unit during osteoarthritis: Structure, function and cartilage bone crosstalk","volume":"12","author":"Goldring","year":"2016","journal-title":"Nat Rev Rheumatol"},{"key":"B17","article-title":"Articular cartilage repair and osteoarthritis","author":"Mankin","year":"2007","journal-title":"Orthop basic Sci Found. Clin Pract"},{"key":"B18","unstructured":"Osteoarthritis is a disease of the osteochondral junction\n          \n          \n            \n              Lozito\n              TP\n            \n            \n              Alexander\n              PG\n            \n            \n              Lin\n              H\n            \n            \n              Gottardi\n              R\n            \n            \n              Cheng\n              AW-M\n            \n            \n              Tuan\n              RS\n            \n          \n          \n          2010"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1155\/2013\/916530","article-title":"The age-related changes in cartilage and osteoarthritis","volume":"2013","author":"Li","year":"2013","journal-title":"BioMed Res Int"},{"key":"B20","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1016\/j.rdc.2010.03.003","article-title":"Bone Damage in rheumatoid arthritis: Mechanistic insights and approaches to prevention","volume":"36","author":"Karmakar","year":"2010","journal-title":"Rheumatol Dis Clin North Am"},{"key":"B21","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1016\/j.bone.2012.01.008","article-title":"Role of bone architecture and anatomy in osteoarthritis","volume":"51","author":"Baker-LePain","year":"2012","journal-title":"Bone"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0173726","article-title":"Subchondral bone histology and grading in osteoarthritis","volume":"12","author":"Aho","year":"2017","journal-title":"PloS One"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1038\/s41584-022-00793-5","article-title":"Mechanisms of joint destruction in rheumatoid arthritis \u2014 immune cell\u2013fibroblast\u2013bone interactions","volume":"18","author":"Komatsu","year":"2022","journal-title":"Nat Rev Rheumatol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.4155\/fso.15.63","article-title":"Animal models are essential to biological research: Issues and perspectives","volume":"1","author":"Barr\u00e9-Sinoussi","year":"2015","journal-title":"Futur. Sci OA"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1186\/s13018-016-0346-5","article-title":"Animal models of osteoarthritis: Classification, update, and measurement of outcomes","volume":"11","author":"Kuyinu","year":"2016","journal-title":"J Orthop Surg Res"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.887460","article-title":"How to model rheumatoid arthritis in animals: from rodents to non-human primates","volume":"13","author":"Zhao","year":"2022","journal-title":"Front Immunol"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2012\/764621","article-title":"A review of translational animal models for knee osteoarthritis","volume":"2012","author":"Gregory","year":"2012","journal-title":"Arthritis"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.knee.2011.07.005","article-title":"A comparative anatomical study of the human knee and six animal species","volume":"19","author":"Proffen","year":"2012","journal-title":"Knee"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1222878110","article-title":"Genomic responses in mouse models poorly mimic human inflammatory diseases","volume":"110","author":"Junhee Seok","year":"2013","journal-title":"Proc Natl Acad Sci U. S. A"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.867015","article-title":"A comprehensive atlas of immunological differences between humans, mice, and non-human primates","volume":"13","author":"Bjornson-Hooper","year":"2022","journal-title":"Front Immunol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2019.101147","article-title":"Human and murine macrophages exhibit differential metabolic responses to lipopolysaccharide - A divergent role for glycolysis","volume":"22","author":"Vijayan","year":"2019","journal-title":"Redox Biol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.172.5.2731","article-title":"Of mice and not men: differences between mouse and human immunology","volume":"172","author":"Mestas","year":"2004","journal-title":"J Immunol"},{"key":"B33","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1089\/ten.teb.2015.0147","article-title":"A road map to commercialization of cartilage therapy in the United States of america","volume":"22","author":"Sridharan","year":"2016","journal-title":"Tissue Eng. Part B Rev"},{"key":"B34","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1016\/j.joca.2021.08.012","article-title":"Pharmacological characterization of GLPG1972\/S201086, a potent and selective small-molecule inhibitor of ADAMTS5","volume":"30","author":"Clement-Lacroix","year":"2022","journal-title":"Osteoarthr. Cartil"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2023.04.001","article-title":"Evaluation of S201086\/GLPG1972, an ADAMTS-5 inhibitor, for the treatment of knee osteoarthritis in ROCCELLA: a phase 2 randomized clinical trial","volume":"31","author":"Schnitzer","year":"2023","journal-title":"Osteoarthr. Cartil"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.090074","article-title":"Anakinra for rheumatoid arthritis: A systematic review","volume":"36","author":"Mertens","year":"2009","journal-title":"J Rheumatol"},{"key":"B37","doi-asserted-by":"publisher","first-page":"1","DOI":"10.4110\/in.2022.22.e8","article-title":"Lessons from the success and failure of targeted drugs for rheumatoid arthritis: perspectives for effective basic and translational research","volume":"22","author":"Kim","year":"2022","journal-title":"Immune Netw"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.755844","article-title":"Toward overcoming treatment failure in rheumatoid arthritis","volume":"12","author":"Wang","year":"2021","journal-title":"Front Immunol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1089\/ten.tec.2017.0189","article-title":"Ethical issues in the use of animal models for tissue engineering: reflections on legal aspects, moral theory, three rs strategies, and harm\u2019Benefit analysis","volume":"23","author":"Liguori","year":"2017","journal-title":"Tissue Eng. - Part C Methods"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.2307\/26580457","article-title":"Recovering the principles of humane experimental technique","volume":"43","author":"Kirk","year":"2018","journal-title":"Science, Technology, & Human Values"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1088\/1758-5090\/ab6a1d","article-title":"Endothelial cells support osteogenesis in an in vitro vascularized bone model developed by 3D bioprinting","volume":"12","author":"Chiesa","year":"2020","journal-title":"Biofabrication"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2021.120773","article-title":"An in vitro chondro-osteo-vascular triphasic model of the osteochondral complex","volume":"272","author":"Pirosa","year":"2021","journal-title":"Biomaterials"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.5114\/reum.2018.75523","article-title":"Cartilage and bone damage in rheumatoid arthritis","volume":"56","author":"Ostrowska","year":"2018","journal-title":"Reumatologia"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1002\/art.37908","article-title":"Adipose-derived mesenchymal stem cells exert antiinflammatory effects on chondrocytes and synoviocytes from osteoarthritis patients through prostaglandin E2","volume":"65","author":"Manferdini","year":"2013","journal-title":"Arthritis Rheumatol"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1007\/s00223-020-00670-x","article-title":"Models of osteoarthritis: relevance and new insights","volume":"109","author":"Samvelyan","year":"2021","journal-title":"Calcif. Tissue Int"},{"key":"B46","doi-asserted-by":"publisher","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":"B47","doi-asserted-by":"publisher","DOI":"10.1186\/1472-6750-11-19","article-title":"Measurement of diffusion in articular cartilage using fluorescence correlation spectroscopy","volume":"11","author":"Lee","year":"2011","journal-title":"BMC Biotechnol"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2020.00750","article-title":"Molecular signaling interactions and transport at the osteochondral interface: A review","volume":"8","author":"Oliveira Silva","year":"2020","journal-title":"Front Cell Dev Biol"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1007\/s10544-019-0373-1","article-title":"Chitosan-based composite bilayer scaffold as an in vitro osteochondral defect regeneration model","volume":"21","author":"Erickson","year":"2019","journal-title":"Biomed Microdevices"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1002\/adhm.202202030","article-title":"An in vitro engineered osteochondral model as tool to study osteoarthritis environment","volume":"12","author":"Scalzone","year":"2023","journal-title":"Adv Healthc. Mater"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0162774","article-title":"Distributed and lumped parameter models for the characterization of high throughput bioreactors","volume":"11","author":"Iannetti","year":"2016","journal-title":"PloS One"},{"key":"B52","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1007\/s10544-018-0264-x","article-title":"Design and validation of an osteochondral bioreactor for the screening of treatments for osteoarthritis","volume":"20","author":"Nichols","year":"2018","journal-title":"Biomed Microdevices"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2014.05.021","article-title":"Human osteoarthritic synovium impacts chondrogenic differentiation of mesenchymal stem cells via macrophage polarisation state","volume":"22","author":"Fahy","year":"2014","journal-title":"Osteoarthr. Cartil"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2020.01.007","article-title":"Macrophages regulate the progression of osteoarthritis","volume":"28","author":"Zhang","year":"2020","journal-title":"Osteoarthr. Cartil"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1021\/mp500136b","article-title":"Stem cell-based microphysiological osteochondral system to model tissue response to interleukin-1B","volume":"11","author":"Lin","year":"2014","journal-title":"Mol Pharm"},{"key":"B56","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.biomaterials.2014.02.012.The","article-title":"Improved angiogenesis in response to localized delivery of macrophage-recruiting molecules","volume":"6","author":"Spiller","year":"2015","journal-title":"PloS One"},{"key":"B57","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.yexcr.2015.10.017","article-title":"Differential gene expression in human, murine, and cell line-derived macrophages upon polarization","volume":"347","author":"Spiller","year":"2016","journal-title":"Exp Cell Res"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.01097","article-title":"Regulation of human Macrophage M1-M2 Polarization Balance by hypoxia and the Triggering receptor expressed on Myeloid cells-1","volume":"8","author":"Raggi","year":"2017","journal-title":"Front Immunol"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-019-03235-w","article-title":"CCL21\/CCR7 signaling in macrophages promotes joint inflammation and Th17-mediated osteoclast formation in rheumatoid arthritis","volume":"77","author":"Van Raemdonck","year":"2020","journal-title":"Cell Mol Life Sci"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2567.2011.03541.x","article-title":"The chemokine CCL18 causes maturation of cultured monocytes to macrophages in the M2 spectrum","volume":"135","author":"Schraufstatter","year":"2012","journal-title":"Immunology"},{"key":"B61","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/srep35855","article-title":"Fucoidan inhibits CCL22 production through NF-\u03baB pathway in M2 macrophages: A potential therapeutic strategy for cancer","volume":"6","author":"Sun","year":"2016","journal-title":"Sci Rep"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2474-12-31","article-title":"In-vivo generation of bone via endochondral ossification by in-vitro chondrogenic priming of adult human and rat mesenchymal stem cells","volume":"12","author":"Farrell","year":"2011","journal-title":"BMC Musculoskeletal Disorders"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.22203\/eCM.v024a16","article-title":"Interleukin-1\u03b2 modulates endochondral ossification by human adult bone marrow stromal cells","volume":"24","author":"Mumme","year":"2012","journal-title":"Eur Cells Mater"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1038\/IJOS.2015.14","article-title":"The Hedgehog signalling pathway in bone formation","volume":"7","author":"Yang","year":"2015","journal-title":"Int J  Sci"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-07-2126","article-title":"Osteopontin promotes vascular endothelial growth factor-dependent breast tumor growth and angiogenesis via autocrine and paracrine mechanisms","volume":"68","author":"Chakraborty","year":"2008","journal-title":"Cancer Res"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1089\/ten.teb.2012.0012","article-title":"Vascularized bone tissue engineering: Approaches for potential improvement","volume":"18","author":"Nguyen","year":"2012","journal-title":"Tissue Eng. - Part B Rev"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1089\/ten.tea.2013.0740","article-title":"Dual-phase osteogenic and vasculogenic engineered tissue for bone formation","volume":"21","author":"Rao","year":"2015","journal-title":"Tissue Eng. - Part A"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1242\/dev.139253","article-title":"Deposition of collagen type I onto skeletal endothelium reveals a new role for blood vessels in regulating bone morphology","volume":"143","author":"Shoham","year":"2016","journal-title":"Dev"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0028352","article-title":"In vitro model of vascularized bone: Synergizing vascular development and osteogenesis","volume":"6","author":"Correia","year":"2011","journal-title":"PloS One"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1016\/j.avsg.2007.11.002","article-title":"Vascular endothelial growth factor induces extracellular matrix proteins and osteopontin in the umbilical artery","volume":"22","author":"Infanger","year":"2008","journal-title":"Ann Vasc Surg"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2013.00106","article-title":"Bone vascularization in normal and disease conditions","volume":"4","author":"Carulli","year":"2013","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.1016\/j.actbio.2022.08.051","article-title":"Biofabricating the vascular tree in engineered bone tissue","volume":"156","author":"de Silva","year":"2023","journal-title":"Acta Biomater"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.3389\/fbioe.2023.1291969","article-title":"Research progress of vascularization strategies of tissue-engineered bone","volume":"11","author":"Lv","year":"2023","journal-title":"Front Bioeng. Biotechnol"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a021899","article-title":"Bone morphogenetic proteins","volume":"8","author":"Katagiri","year":"2016","journal-title":"Cold Spring Harb. Perspect Biol"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2018.03.007","article-title":"Bone morphogenetic proteins for articular cartilage regeneration","volume":"26","author":"Deng","year":"2018","journal-title":"Osteoarthr. Cartil"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.3390\/cells10081903","article-title":"An in vitro system to study the effect of subchondral bone health on articular cartilage repair in humans","volume":"10","author":"Hopkins","year":"2021","journal-title":"Cells"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.4171","article-title":"Bone vasculature and bone marrow vascular niches in health and disease","volume":"35","author":"Chen","year":"2020","journal-title":"J Bone Miner. Res"},{"key":"B78","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-13417-w","article-title":"Vascular endothelial growth factor in cartilage development and osteoarthritis","volume":"7","author":"Nagao","year":"2017","journal-title":"Sci Rep"},{"key":"B79","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s13287-015-0065-6","article-title":"Endothelial cells direct human mesenchymal stem cells for osteo- and chondro-lineage differentiation through endothelin-1 and AKT signaling","volume":"6","author":"Tsai","year":"2015","journal-title":"Stem Cell Res Ther"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.25623.Chondrogenesis","article-title":"Chondrogenesis of embryonic stem cell-derived mesenchymal stem cells induced by TGF\u03b21 and BMP7 through increased TGF\u03b2 Receptor expression and endogenous TGF\u03b21 production","volume":"176","author":"Lee","year":"2017","journal-title":"J Cell Biochem"},{"key":"B81","doi-asserted-by":"publisher","DOI":"10.3390\/jcm8091343","article-title":"Synovial cytokines significantly correlate with osteoarthritis-related knee pain and disability: Inflammatory mediators of potential clinical relevance","volume":"8","author":"Nees","year":"2019","journal-title":"J Clin Med"},{"key":"B82","doi-asserted-by":"publisher","DOI":"10.3390\/jcm10215027","article-title":"Synovial fluid cytokines, chemokines and mmp levels in osteoarthritis patients with knee pain display a profile similar to many rheumatoid arthritis patients","volume":"10","author":"Meehan","year":"2021","journal-title":"J Clin Med"},{"key":"B83","doi-asserted-by":"publisher","DOI":"10.1016\/j.cyto.2021.155546","article-title":"Extensive cytokine analysis in synovial fluid of osteoarthritis patients","volume":"143","author":"Yang","year":"2021","journal-title":"Cytokine"},{"key":"B84","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbiomech.2023.111673","article-title":"Computational and experimental characterizations of the spatiotemporal activity and functional role of TGF-\u03b2 in the synovial joint","volume":"156","author":"Dogru","year":"2023","journal-title":"J Biomech"},{"key":"B85","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1089\/ten.tea.2023.0360","article-title":"Physiologic doses of transforming growth factor-\u03b2 Improve the composition of engineered articular cartilage","volume":"31","author":"Wang","year":"2024","journal-title":"Tissue Eng. - Part A"},{"key":"B86","doi-asserted-by":"publisher","DOI":"10.1089\/adt.2014.573","article-title":"Three-dimensional cell culture systems and their applications in drug discovery and cell-based biosensors","volume":"12","author":"Edmondson","year":"2014","journal-title":"Assay Drug Dev Technol"},{"key":"B87","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/srep30956","article-title":"Simulated microgravity and 3D culture enhance induction, viability, proliferation and differentiation of cardiac progenitors from human pluripotent stem cells","volume":"6","author":"Jha","year":"2016","journal-title":"Sci Rep"},{"key":"B88","doi-asserted-by":"publisher","DOI":"10.2460\/ajvr.2000.61.624","article-title":"Effects of interleukin-1\u03b2 \u03b2 and tumor necrosis factor-\u03b1 \u03b1 on expression of matrix-related genes by cultured equine articular chondrocytes","volume":"61","author":"Richardson","year":"2000","journal-title":"American Journal of Veterinary Research"},{"key":"B89","doi-asserted-by":"publisher","DOI":"10.3389\/fbioe.2023.1167623","article-title":"A cytokine-induced spheroid-based in vitro model for studying osteoarthritis pathogenesis","volume":"11","author":"Scalzone","year":"2023","journal-title":"Front Bioeng. Biotechnol"},{"key":"B90","unstructured":"Cross-talk between IL-1 and IL-6 signaling pathways in rheumatoid arthritis synovial fibroblasts 1\n          \n          \n            \n              Deon\n              D\n            \n            \n              Ahmed\n              S\n            \n            \n              Tai\n              K\n            \n            \n              Scaletta\n              N\n            \n            \n              Herrero\n              C\n            \n            \n              Lee\n              I-H\n            \n          \n          \n          2001"},{"key":"B91","doi-asserted-by":"publisher","DOI":"10.1302\/2046-3758.117.BJR-2021-0481.R1","article-title":"Analysis of combined deficiency ofinterleukin-\u00ad1 and -6 versus singledeficiencies in TNF-\u00admediated arthritis and systemic bone loss","volume":"11","author":"Hayer","year":"2022","journal-title":"Bone Joint Res"},{"key":"B92","doi-asserted-by":"publisher","first-page":"473","DOI":"10.6084\/m9.figshare.12581825","article-title":"Understanding the role of interleukin-6 (IL-6) in the joint and beyond: A comprehensive review of IL-6 inhibition for the management of rheumatoid arthritis","volume":"7","author":"Favalli","year":"2020","journal-title":"Rheumatology and Therapy"},{"key":"B93","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.905356","article-title":"Synovial macrophages: past life, current situation, and application in inflammatory arthritis","volume":"13","author":"Bai","year":"2022","journal-title":"Front Immunol"},{"key":"B94","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1164137","article-title":"Effects of synovial macrophages in osteoarthritis","volume":"14","author":"Zhao","year":"2023","journal-title":"Front Immunol"},{"key":"B95","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/keae161","article-title":"Transcriptomic profiling of osteoarthritis synovial macrophages reveals a tolerized phenotype compounded by a weak corticosteroid response","volume":"64","author":"Wang","year":"2024","journal-title":"Rheumatology"},{"key":"B96","doi-asserted-by":"publisher","DOI":"10.1042\/CS20220531","article-title":"M1\/M2 macrophages and their overlaps - myth or reality","volume":"137","author":"Strizova","year":"2023","journal-title":"Clin Sci"},{"key":"B97","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0045466","article-title":"High-resolution transcriptome of human macrophages","volume":"7","author":"Beyer","year":"2012","journal-title":"PloS One"},{"key":"B98","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2014.00491","article-title":"Macrophage cytokines: Involvement in immunity and infectious diseases","volume":"5","author":"Duque","year":"2014","journal-title":"Front Immunol"},{"key":"B99","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2015.00263","article-title":"Much more than M1 and M2 macrophages, there are also CD169+ and TCR+ macrophages","volume":"6","author":"Ch\u00e1vez-Gal\u00e1n","year":"2015","journal-title":"Front Immunol"},{"key":"B100","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/metabo10110429","article-title":"Nitric oxide in macrophage immunometabolism: Hiding in plain sight","volume":"10","author":"Palmieri","year":"2020","journal-title":"Metabolites"},{"key":"B101","doi-asserted-by":"publisher","DOI":"10.1097\/00002281-199805000-00018","article-title":"The role of nitric oxide in articular cartilage breakdown in osteoarthritis","volume":"10","author":"Amin","year":"1998","journal-title":"Curr Opin Rheumatol"},{"key":"B102","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2020.09.005","article-title":"Identification of tissue-dependent proteins in knee OA synovial fluid","volume":"29","author":"Timur","year":"2021","journal-title":"Osteoarthr. Cartil"},{"key":"B103","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.108.173898","article-title":"Metalloproteinase expression in monocytes and macrophages and its relationship to atherosclerotic plaque instability","volume":"28","author":"Newby","year":"2008","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"B104","doi-asserted-by":"publisher","first-page":"1-9","DOI":"10.1016\/j.bonr.2019.100207","article-title":"Bone morphogenetic proteins: Their role in regulating osteoclast differentiation","volume":"10","author":"Huntley","year":"2019","journal-title":"Bone Rep"},{"key":"B105","doi-asserted-by":"publisher","DOI":"10.1359\/jbmr.060109","article-title":"BMP signaling is required for RUNX2-dependent induction of the osteoblast phenotype","volume":"21","author":"Phimphilai","year":"2006","journal-title":"J Bone Miner. Res"},{"key":"B106","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0214709","article-title":"Co-culture of osteochondral explants and synovial membrane as in vitro model for osteoarthritis","volume":"14","author":"Haltmayer","year":"2019","journal-title":"PloS One"},{"key":"B107","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2021.02.270","article-title":"A novel osteochondral explant model to study bone and cartilage responses to damage in PTOA","volume":"29","author":"Amado","year":"2021","journal-title":"Osteoarthr. Cartil"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1495613\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,26]],"date-time":"2025-05-26T01:17:58Z","timestamp":1748222278000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1495613\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,26]]},"references-count":107,"alternative-id":["10.3389\/fimmu.2025.1495613"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1495613","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,26]]},"article-number":"1495613"}}