{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T08:17:49Z","timestamp":1787905069899,"version":"build-2784847793"},"reference-count":41,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,2,17]],"date-time":"2023-02-17T00:00:00Z","timestamp":1676592000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health","award":["UG3\/UH3 TR002136"],"award-info":[{"award-number":["UG3\/UH3 TR002136"]}]},{"name":"National Institutes of Health","award":["UG3\/UH3 TR003090"],"award-info":[{"award-number":["UG3\/UH3 TR003090"]}]},{"name":"National Institutes of Health","award":["T32 EB001026"],"award-info":[{"award-number":["T32 EB001026"]}]},{"name":"National Institutes of Health","award":["W81XWH2010902"],"award-info":[{"award-number":["W81XWH2010902"]}]},{"DOI":"10.13039\/100000005","name":"US Department of Defense","doi-asserted-by":"publisher","award":["UG3\/UH3 TR002136"],"award-info":[{"award-number":["UG3\/UH3 TR002136"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000005","name":"US Department of Defense","doi-asserted-by":"publisher","award":["UG3\/UH3 TR003090"],"award-info":[{"award-number":["UG3\/UH3 TR003090"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000005","name":"US Department of Defense","doi-asserted-by":"publisher","award":["T32 EB001026"],"award-info":[{"award-number":["T32 EB001026"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000005","name":"US Department of Defense","doi-asserted-by":"publisher","award":["W81XWH2010902"],"award-info":[{"award-number":["W81XWH2010902"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Osteoarthritis (OA) is a painful and disabling joint disease affecting millions worldwide. The lack of clinically relevant models limits our ability to predict therapeutic outcomes prior to clinical trials, where most drugs fail. Therefore, there is a need for a model that accurately recapitulates the whole-joint disease nature of OA in humans. Emerging microphysiological systems provide a new opportunity. We recently established a miniature knee joint system, known as the miniJoint, in which human bone-marrow-derived mesenchymal stem cells (hBMSCs) were used to create an osteochondral complex, synovial-like fibrous tissue, and adipose tissue analogs. In this study, we explored the potential of the miniJoint in developing novel treatments for OA by testing the hypothesis that co-treatment with anti-inflammation and chondroinducing agents can suppress joint inflammation and associated cartilage degradation. Specifically, we created a \u201csynovitis\u201d-relevant OA model in the miniJoint by treating synovial-like tissues with interleukin-1\u03b2 (IL-1\u03b2), and then a combined treatment of oligodeoxynucleotides (ODNs) suppressing the nuclear factor kappa beta (NF-\u03baB) genetic pathway and bone morphogenic protein-7 (BMP-7) was introduced. The combined treatment with BMP-7 and ODNs reduced inflammation in the synovial-like fibrous tissue and showed an increase in glycosaminoglycan formation in the cartilage portion of the osteochondral complex. For the first time, this study demonstrated the potential of the miniJoint in developing disease-modifying OA drugs. The therapeutic efficacy of co-treatment with NF-\u03baB ODNs and BMP-7 can be further validated in future clinical studies.<\/jats:p>","DOI":"10.3390\/biom13020384","type":"journal-article","created":{"date-parts":[[2023,2,17]],"date-time":"2023-02-17T03:27:41Z","timestamp":1676604461000},"page":"384","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Using Microphysiological System for the Development of Treatments for Joint Inflammation and Associated Cartilage Loss\u2014A Pilot Study"],"prefix":"10.3390","volume":"13","author":[{"given":"Meagan J.","family":"Makarczyk","sequence":"first","affiliation":[{"name":"Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, 450 Technology Drive, Rm 217, Pittsburgh, PA 15219, USA"},{"name":"Department of Bioengineering, University of Pittsburgh Swanson School of Engineering, 450 Technology Drive, Rm 217, Pittsburgh, PA 15219, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Hines","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, 450 Technology Drive, Rm 217, Pittsburgh, PA 15219, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haruyo","family":"Yagi","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, 450 Technology Drive, Rm 217, Pittsburgh, PA 15219, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6009-629X","authenticated-orcid":false,"given":"Zhong Alan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, 450 Technology Drive, Rm 217, Pittsburgh, PA 15219, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alyssa M.","family":"Aguglia","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, 450 Technology Drive, Rm 217, Pittsburgh, PA 15219, USA"},{"name":"Department of Bioengineering, University of Pittsburgh Swanson School of Engineering, 450 Technology Drive, Rm 217, Pittsburgh, PA 15219, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin","family":"Zbikowski","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, 450 Technology Drive, Rm 217, Pittsburgh, PA 15219, USA"},{"name":"Department of Bioengineering, University of Pittsburgh Swanson School of Engineering, 450 Technology Drive, Rm 217, Pittsburgh, PA 15219, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne-Marie","family":"Padget","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, 450 Technology Drive, Rm 217, Pittsburgh, PA 15219, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0175-566X","authenticated-orcid":false,"given":"Qi","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Stanford University, Stanford, CA 94350, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6196-3722","authenticated-orcid":false,"given":"Bruce A.","family":"Bunnell","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology, and Genetics University of North Texas Health Science Center, Fort Worth, TX 76107, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1919-3717","authenticated-orcid":false,"given":"Stuart B.","family":"Goodman","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Stanford University, Stanford, CA 94350, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hang","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, 450 Technology Drive, Rm 217, Pittsburgh, PA 15219, USA"},{"name":"Department of Orthopaedic Surgery, Stanford University, Stanford, CA 94350, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1136\/annrheumdis-2019-216515","article-title":"Global, regional and national burden of osteoarthritis 1990-2017: A systematic analysis of the Global Burden of Disease Study 2017","volume":"79","author":"Safiri","year":"2020","journal-title":"Ann. Rheum. Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1159\/000496605","article-title":"Cell Therapy for Knee Osteoarthritis: Mesenchymal Stromal Cells","volume":"65","author":"Kim","year":"2019","journal-title":"Gerontology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e892","DOI":"10.1097\/PR9.0000000000000892","article-title":"Neuroimmune interactions and osteoarthritis pain: Focus on macrophages","volume":"6","author":"Geraghty","year":"2021","journal-title":"Pain Rep."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1089\/ten.tec.2020.0309","article-title":"Current Models for Development of Disease-Modifying Osteoarthritis Drugs","volume":"27","author":"Makarczyk","year":"2021","journal-title":"Tissue Eng. Part C Methods"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"He, Y., Li, Z., Alexander, P.G., Ocasio-Nieves, B.D., Yocum, L., Lin, H., and Tuan, R.S. (2020). Pathogenesis of Osteoarthritis: Risk Factors, Regulatory Pathways in Chondrocytes, and Experimental Models. Biology, 9.","DOI":"10.3390\/biology9080194"},{"key":"ref_6","first-page":"00193-7","article-title":"Synovial joint-on-a-chip for modeling arthritis: Progress, pitfalls, and potential","volume":"22","author":"Li","year":"2022","journal-title":"Trends Biotechnol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"4597","DOI":"10.1016\/j.cell.2021.08.005","article-title":"Organs-on-a-chip models for biological research","volume":"184","author":"Radisic","year":"2021","journal-title":"Cell"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1021\/bp034077d","article-title":"The design and fabrication of three-chamber microscale cell culture analog devices with integrated dissolved oxygen sensors","volume":"20","author":"Sin","year":"2004","journal-title":"Biotechnol. Prog."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e2105909","DOI":"10.1002\/advs.202105909","article-title":"Human Mesenchymal Stem Cell-Derived Miniature Joint System for Disease Modeling and Drug Testing","volume":"9","author":"Li","year":"2022","journal-title":"Adv. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1080\/13543784.2018.1539075","article-title":"Investigational drugs for the treatment of osteoarthritis, an update on recent developments","volume":"27","author":"Zhu","year":"2018","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Hunter, D.J., Pike, M.C., Jonas, B.L., Kissin, E., Krop, J., and McAlindon, T. (2010). Phase 1 safety and tolerability study of BMP-7 in symptomatic knee osteoarthritis. BMC Musculoskelet. Disord., 11.","DOI":"10.1186\/1471-2474-11-232"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1007\/s12178-020-09664-6","article-title":"Current Applications of Growth Factors for Knee Cartilage Repair and Osteoarthritis Treatment","volume":"13","author":"Shah","year":"2020","journal-title":"Curr. Rev. Musculoskelet. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"100240","DOI":"10.1016\/j.ocarto.2022.100240","article-title":"Sustained delivery of the bone morphogenetic proteins BMP-2 and BMP-7 for cartilage repair and regeneration in osteoarthritis","volume":"4","author":"Whitty","year":"2022","journal-title":"Osteoarthr. Cartil. Open"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3872","DOI":"10.1002\/jbm.a.35532","article-title":"NF-kappaB decoy oligodeoxynucleotide inhibits wear particle-induced inflammation in a murine calvarial model","volume":"103","author":"Sato","year":"2015","journal-title":"J. Biomed. Mater. Res. A"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1828","DOI":"10.1002\/jbm.a.37175","article-title":"Suppression of NF-kappaB-induced chronic inflammation mitigates inflammatory osteolysis in the murine continuous polyethylene particle infusion model","volume":"109","author":"Utsunomiya","year":"2021","journal-title":"J. Biomed. Mater. Res. A"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2402","DOI":"10.1089\/ten.tea.2013.0642","article-title":"Cartilage tissue engineering application of injectable gelatin hydrogel with in situ visible-light-activated gelation capability in both air and aqueous solution","volume":"20","author":"Lin","year":"2014","journal-title":"Tissue Eng. Part A"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2203","DOI":"10.1021\/mp500136b","article-title":"Stem cell-based microphysiological osteochondral system to model tissue response to interleukin-1beta","volume":"11","author":"Lin","year":"2014","journal-title":"Mol. Pharm."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1111\/j.1348-0421.2006.tb03827.x","article-title":"Regulation of NF-kappaB signaling by decoy oligodeoxynucleotides","volume":"50","author":"Isomura","year":"2006","journal-title":"Microbiol. Immunol."},{"key":"ref_19","first-page":"1","article-title":"Age-related degeneration of articular cartilage in the pathogenesis of osteoarthritis: Molecular markers of senescent chondrocytes","volume":"30","author":"Musumeci","year":"2015","journal-title":"Histol. Histopathol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1050","DOI":"10.1016\/j.joca.2022.03.012","article-title":"Advances in organ-on-a-chip systems for modelling joint tissue and osteoarthritic diseases","volume":"30","author":"Banh","year":"2022","journal-title":"Osteoarthr. Cartil."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1038\/s41584-021-00736-6","article-title":"Joint-on-chip platforms: Entering a new era of in vitro models for arthritis","volume":"18","author":"Paggi","year":"2022","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"411","DOI":"10.3389\/fbioe.2019.00411","article-title":"Osteochondral Tissue Chip Derived From iPSCs: Modeling OA Pathologies and Testing Drugs","volume":"7","author":"Lin","year":"2019","journal-title":"Front. Bioeng. Biotechnol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1038\/s41551-019-0406-3","article-title":"Hyperphysiological compression of articular cartilage induces an osteoarthritic phenotype in a cartilage-on-a-chip model","volume":"3","author":"Occhetta","year":"2019","journal-title":"Nat. Biomed. Eng."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1186\/s13075-022-02881-z","article-title":"Inflammatory cytokines and mechanical injury induce post-traumatic osteoarthritis-like changes in a human cartilage-bone-synovium microphysiological system","volume":"24","author":"Dwivedi","year":"2022","journal-title":"Arthritis. Res. Ther."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"045001","DOI":"10.1088\/1758-5090\/ac0c5e","article-title":"Recapitulating monocyte extravasation to the synovium in an organotypic microfluidic model of the articular joint","volume":"13","author":"Mondadori","year":"2021","journal-title":"Biofabrication"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"100023","DOI":"10.1016\/j.mtbio.2019.100023","article-title":"Microfluidic nutrient gradient-based three-dimensional chondrocyte culture-on-a-chip as an in vitro equine arthritis model","volume":"4","author":"Rosser","year":"2019","journal-title":"Mater. Today Bio"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4128","DOI":"10.1039\/D1LC00130B","article-title":"Establishment of a human three-dimensional chip-based chondro-synovial coculture joint model for reciprocal cross talk studies in arthritis research","volume":"21","author":"Rothbauer","year":"2021","journal-title":"Lab Chip"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/S0925-4439(02)00158-8","article-title":"Age-related changes in cartilage endogenous osteogenic protein-1 (OP-1)","volume":"1588","author":"Chubinskaya","year":"2002","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_29","first-page":"103","article-title":"Regulation of anabolic and catabolic gene expression in normal and osteoarthritic adult human articular chondrocytes by osteogenic protein-1","volume":"22","author":"Fan","year":"2004","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1080\/08977190802291733","article-title":"Effects induced by BMPS in cultures of human articular chondrocytes: Comparative studies","volume":"26","author":"Chubinskaya","year":"2008","journal-title":"Growth Factors"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1016\/j.biopha.2006.09.001","article-title":"Bone morphogenetic protein 7 (bmp-7) stimulates proteoglycan synthesis in human osteoarthritic chondrocytes in vitro","volume":"60","author":"Stove","year":"2006","journal-title":"Biomed. Pharmacother."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1007\/s00264-007-0423-9","article-title":"OP-1\/BMP-7 in cartilage repair","volume":"31","author":"Chubinskaya","year":"2007","journal-title":"Int. Orthop."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1016\/j.joca.2013.01.009","article-title":"Hypertrophic differentiation during chondrogenic differentiation of progenitor cells is stimulated by BMP-2 but suppressed by BMP-7","volume":"21","author":"Caron","year":"2013","journal-title":"Osteoarthr. Cartil."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"431","DOI":"10.3389\/fendo.2019.00431","article-title":"Emerging Trend in the Pharmacotherapy of Osteoarthritis","volume":"10","author":"Zhang","year":"2019","journal-title":"Front. Endocrinol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Jimi, E., Fei, H., and Nakatomi, C. (2019). NF-kappaB Signaling Regulates Physiological and Pathological Chondrogenesis. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20246275"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1186\/s10020-021-00329-9","article-title":"Danshensu inhibits the IL-1beta-induced inflammatory response in chondrocytes and osteoarthritis possibly via suppressing NF-kappaB signaling pathway","volume":"27","author":"Xu","year":"2021","journal-title":"Mol. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"16475","DOI":"10.1038\/s41598-018-34830-9","article-title":"Intra-articular administration of IkappaBalpha kinase inhibitor suppresses mouse knee osteoarthritis via downregulation of the NF-kappaB\/HIF-2alpha axis","volume":"8","author":"Murahashi","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1002\/art.23211","article-title":"Differential requirements for IKKalpha and IKKbeta in the differentiation of primary human osteoarthritic chondrocytes","volume":"58","author":"Olivotto","year":"2008","journal-title":"Arthritis Rheum."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"4039472","DOI":"10.1155\/2019\/4039472","article-title":"Trans-Cinnamaldehyde Inhibits IL-1beta-Stimulated Inflammation in Chondrocytes by Suppressing NF-kappaB and p38-JNK Pathways and Exerts Chondrocyte Protective Effects in a Rat Model of Osteoarthritis","volume":"2019","author":"Xia","year":"2019","journal-title":"BioMed Res. Int."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"555","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":"ref_41","doi-asserted-by":"crossref","first-page":"111","DOI":"10.3389\/fimmu.2020.00111","article-title":"Macrophage: A Potential Target on Cartilage Regeneration","volume":"11","author":"Fernandes","year":"2020","journal-title":"Front. Immunol."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/13\/2\/384\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:39:14Z","timestamp":1760121554000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/13\/2\/384"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,17]]},"references-count":41,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["biom13020384"],"URL":"https:\/\/doi.org\/10.3390\/biom13020384","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,17]]}}}