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How physiological loads are accommodated in the healthy joint and how regionalized architectural alterations reconfigure joint\u2010level mechanics to promote OA, however, remain unresolved. Here, we integrate in situ mechanical loading of murine tibial epiphyses with phase\u2010contrast synchrotron X\u2010ray computed tomography and digital volume correlation to quantify three\u2010dimensional, compartment\u2010specific load\u2010bearing behavior in intact healthy (CBA) and OA\u2010prone (STR\/Ort) knee joints. We find that raised focal strain concentrations emerge within the subchondral plate and precede histological cartilage degeneration in STR\/Ort joints at 10 weeks of age. In contrast, these strain concentrations are absent in both young and aging CBA mice, where mechanical strain is preferentially transmitted to locations distant from the articular surface. Finite element modeling further reveals that strain localization in STR\/Ort joints is governed by region\u2010specific microstructural incongruities. Together, these findings demonstrate that epiphyseal microarchitecture preserves mechanical homeostasis during healthy aging, whereas spatial disorganization of subchondral microarchitecture renders the epiphysis susceptible to load\u2010induced failure. Collectively, this work identifies mechano\u2010architectural misalignment within the mineralized phase of the tibial epiphysis as an early mechanical promoter of OA emergence.<\/jats:p>","DOI":"10.1002\/advs.76716","type":"journal-article","created":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T19:22:41Z","timestamp":1784834561000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["In Situ Profiling of Nanoscale Strains Uncovers Mechano\u2010Architectural Predictors of Aging and Osteoarthritis Emergence"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5449-358X","authenticated-orcid":false,"given":"Aikta","family":"Sharma","sequence":"first","affiliation":[{"name":"Department of Mechanical Engineering University College London  London UK"},{"name":"Research Complex at Harwell Rutherford Appleton Laboratory  Didcot UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3411-1684","authenticated-orcid":false,"given":"Lucinda A. E.","family":"Evans","sequence":"additional","affiliation":[{"name":"Centre for Lifelong Health School of Applied Sciences University of Brighton  Brighton UK"},{"name":"Comparative Biomedical Sciences Royal Veterinary College  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3352-4946","authenticated-orcid":false,"given":"Lucie E.","family":"Bourne","sequence":"additional","affiliation":[{"name":"Centre for Lifelong Health School of Applied Sciences University of Brighton  Brighton UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1784-319X","authenticated-orcid":false,"given":"Jishizhan","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Mechanical Engineering University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9836-8932","authenticated-orcid":false,"given":"Alissa L.","family":"Parmenter","sequence":"additional","affiliation":[{"name":"Department of Mechanical Engineering University College London  London UK"},{"name":"Research Complex at Harwell Rutherford Appleton Laboratory  Didcot UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8424-9510","authenticated-orcid":false,"given":"Joseph","family":"Brunet","sequence":"additional","affiliation":[{"name":"Department of Mechanical Engineering University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kamel","family":"Madi","sequence":"additional","affiliation":[{"name":"3Dmagination Ltd Rutherford Appleton Laboratory  Didcot UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4537-210X","authenticated-orcid":false,"given":"Sebastian","family":"Marussi","sequence":"additional","affiliation":[{"name":"Department of Mechanical Engineering University College London  London UK"},{"name":"Research Complex at Harwell Rutherford Appleton Laboratory  Didcot UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3861-998X","authenticated-orcid":false,"given":"Andrew A.","family":"Pitsillides","sequence":"additional","affiliation":[{"name":"Comparative Biomedical Sciences Royal Veterinary College  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3898-8881","authenticated-orcid":false,"given":"Peter D.","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Mechanical Engineering University College London  London UK"},{"name":"Research Complex at Harwell Rutherford Appleton Laboratory  Didcot UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8492-9778","authenticated-orcid":false,"given":"Katherine A.","family":"Staines","sequence":"additional","affiliation":[{"name":"Centre for Lifelong Health School of Applied Sciences University of Brighton  Brighton UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,23]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aao2189"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.matsci.28.1.271"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140\u20106736(19)30417\u20109"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2665\u20109913(23)00163\u20107"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.41142"},{"key":"e_1_2_11_7_1","first-page":"135","article-title":"Disease Modification in Osteoarthritis: Are We There Yet?","volume":"37","author":"Oo W. 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