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However, the molecular links between aberrant mechanics and OA initiation\/progression remain unclear due to the lack of human models capturing the interplay of joint tissues in a mechanically active environment. Replicating the strain gradient across the osteochondral interface remains an unmet challenge. Here, an OsteoChondral Unit (OCU)\u2010on\u2010Chip platform is engineered and functionally validated where composite hyaline cartilage\u2010mineralized subchondral microtissues are exposed to strain\u2010controlled, tissue\u2010specific compression levels akin, respectively, to those of cartilage and of the mineralized tissue at the osteochondral interface in vivo. Upon hyperphysiological loading of the OCU\u2010on\u2010Chip, an increase in the release and accumulation of calcium crystals, as reported in OA patients, is observed. Using single\u2010cell RNA sequencing, the role of the mineralized subchondral layer in sustaining chondrocyte subpopulations implicated in OA is demonstrated, and an overview of the transcriptional machinery activated by mechanical overstimulation is provided. The OCU\u2010on\u2010Chip captures clinically observed changes including alterations in ribosome biogenesis and apoptosis\u2010related pathways. Thus, it represents a valuable model for investigating mechanisms upstream of cartilage degeneration and may facilitate the identification of novel druggable biological pathways.<\/jats:p>","DOI":"10.1002\/adhm.202501588","type":"journal-article","created":{"date-parts":[[2025,6,25]],"date-time":"2025-06-25T04:08:19Z","timestamp":1750824499000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["An Organ\u2010on\u2010Chip Platform for Strain\u2010Controlled, Tissue\u2010Specific Compression of Cartilage and Mineralized Osteochondral Interface to Study Mechanical Overloading in Osteoarthritis"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8228-6441","authenticated-orcid":false,"given":"Andrea","family":"Mainardi","sequence":"first","affiliation":[{"name":"Department of Biomedicine University Hospital Basel University of Basel  Hebelstrasse 20 Basel 4031 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