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Articular cartilage degradation is a hallmark, resulting from an imbalance in extracellular matrix turnover, influenced by mechanical and biochemical signals. The synovium also plays a central role in joint inflammation, with macrophages and fibroblasts releasing pro\u2010inflammatory cytokines and degradative enzymes. However, understanding cartilage\u2010synovium interactions in OA pathogenesis remains challenging. Here, a compartmentalized joint\u2010on\u2010chip (JoC) model that enables independent culture of 3D human cartilage and synovium constructs, allowing spatio\u2010temporal control over their communication, is presented. The JoC platform supports induction of OA characteristics in both tissues, by applying hyper\u2010physiological compression to cartilage constructs to mimic mechanical damage and by treating synovium constructs with TNF\u03b1 and IFN\u03b3 to simulate inflammation. Moreover, the platform enables exploration of paracrine signaling between these tissues under pathophysiological conditions, showing that inflamed synovium constructs induce early cartilage degradation, while mechanically damaged cartilage promotes macrophage activation and inflammatory responses in the synovium. These findings support a bidirectional relationship in OA onset and underscore the JoC model as a tool for studying joint tissue interactions.<\/jats:p>","DOI":"10.1002\/advs.202500374","type":"journal-article","created":{"date-parts":[[2025,9,12]],"date-time":"2025-09-12T03:42:23Z","timestamp":1757648543000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["A Compartmentalized Joint\u2010on\u2010chip (JoC) Model to Unravel the Contribution of Cartilage and Synovium to Osteoarthritis Pathogenesis"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9517-1803","authenticated-orcid":false,"given":"Cecilia","family":"Palma","sequence":"first","affiliation":[{"name":"Department of Electronics Information and Bioengineering Politecnico di Milano  Via Ponzio 34\/5 Milan 20133 Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5655-5302","authenticated-orcid":false,"given":"Shima","family":"Salehi","sequence":"additional","affiliation":[{"name":"Cell and Tissue Engineering Laboratory IRCCS Istituto Ortopedico Galeazzi  Via Cristina Belgioioso 173 Milan 20157 Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9162-6855","authenticated-orcid":false,"given":"Michela Anna","family":"Polidoro","sequence":"additional","affiliation":[{"name":"Hepatobiliary Immunopathology Laboratory IRCCS Humanitas Research Hospital  Via Alessandro Manzoni, 56 Rozzano Milan 20089 Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7301-1208","authenticated-orcid":false,"given":"Matteo","family":"Moretti","sequence":"additional","affiliation":[{"name":"Cell and Tissue Engineering Laboratory IRCCS Istituto Ortopedico Galeazzi  Via Cristina Belgioioso 173 Milan 20157 Italy"},{"name":"Regenerative Medicine Division, Institute for Translational Research Ente Ospedaliero Cantonale \u2013 Universit\u00e0 della Svizzera Italiana  Via Chiesa 5 Bellinzona 6500 Switzerland"},{"name":"Euler Institute, Faculty of Biomedical Sciences Universit\u00e0 della Svizzera Italiana (USI)  Via Buffi 13 Lugano 6900 Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2904-8652","authenticated-orcid":false,"given":"Marco","family":"Rasponi","sequence":"additional","affiliation":[{"name":"Department of Electronics Information and Bioengineering Politecnico di Milano  Via Ponzio 34\/5 Milan 20133 Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0410-5814","authenticated-orcid":false,"given":"Silvia","family":"Lopa","sequence":"additional","affiliation":[{"name":"Cell and Tissue Engineering Laboratory IRCCS Istituto Ortopedico Galeazzi  Via Cristina Belgioioso 173 Milan 20157 Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5758-2019","authenticated-orcid":false,"given":"Paola","family":"Occhetta","sequence":"additional","affiliation":[{"name":"Department of Electronics Information and Bioengineering Politecnico di Milano  Via Ponzio 34\/5 Milan 20133 Italy"},{"name":"BiomimX Srl  Viale Decumano 41, MIND \u2013 Milano Innovation District Milan 20157 Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,9,11]]},"reference":[{"key":"e_1_2_10_1_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2016.72"},{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2016.01.019"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2020.01.002"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(11)60243-2"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.3390\/biology9080194"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-023-01020-1"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2010.197"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2023.01.004"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1186\/ar148"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbapap.2011.06.020"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1053\/joca.1998.0238"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/nyas.13930"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2016.136"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11926-014-0451-6"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1177\/1759720X12467868"},{"key":"e_1_2_10_16_1","first-page":"57","volume":"120","author":"Griffin T. 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