{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T20:46:57Z","timestamp":1789678017031,"version":"4.0.1"},"posted":{"date-parts":[[2024,5,17]]},"group-title":"Physiology","reference-count":51,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,5,17]],"date-time":"2024-05-17T00:00:00Z","timestamp":1715904000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,3,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Purpose<\/jats:title>\n                  <jats:p>Genetic deletion of mTOR has protected against post-traumatic osteoarthritis (OA) in male mice, however, effects of pharmacological mTOR-inhibition are equivocal and have not been tested in aging models nor in female subjects. Therefore, the goal of this study was to determine if mTOR-inhibition by rapamycin can modify OA pathology in aging non-human primates and female mice.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    Common marmosets were administered oral rapamycin (1mg\/kg\/day) or vehicle starting near mid-life until death. Five-month-old, female C57BL\/6J mice were treated with vehicle or rapamycin (IP, 2mg\/kg, 3x\/week) for 8-weeks following non-invasive ACL rupture. Knee OA pathology was assessed via microCT and histology. Phosphorylation of mTORC1 (p-RPS6\n                    <jats:sup>S235\/36<\/jats:sup>\n                    ) and mTORC2 (p-Akt\n                    <jats:sup>S473<\/jats:sup>\n                    , p-NDRG1\n                    <jats:sup>T638<\/jats:sup>\n                    , p-PKC\u03b1\n                    <jats:sup>T348<\/jats:sup>\n                    ) substrates were evaluated via western blot in articular cartilage, meniscus, and\/or infrapatellar fat pad. ATDC5 cells were cultured with rapamycin to determine time and dose effects on mTORC1\/2 signaling.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    In marmosets, rapamycin did not impact age-related radiographic OA severity or cartilage pathology but increased medial meniscus calcification and lowered lateral tibia subchondral thickness, particularly in females. In female mice, rapamycin worsened ACLR-induced meniscus calcification and cartilage pathology. In marmoset and mouse joint tissues, rapamycin inhibited mTORC1 and increased p-Akt\n                    <jats:sup>S473<\/jats:sup>\n                    but not p-NDRG1\n                    <jats:sup>T638<\/jats:sup>\n                    or p-PKC\u03b1\n                    <jats:sup>T348<\/jats:sup>\n                    . This mTOR signaling pattern was replicated in ATDC5 cells during exposure to low concentrations of rapamycin.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>\n                    Rapamycin attenuated mTORC1 signaling with feedback activation of Akt\n                    <jats:sup>S473<\/jats:sup>\n                    in articular cartilage, meniscus, and\/or infrapatellar fat pad and was accompanied by deleterious effects on meniscus calcification and\/or cartilage pathology in female mice and common marmosets.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2024.05.14.594256","type":"posted-content","created":{"date-parts":[[2024,5,17]],"date-time":"2024-05-17T15:35:10Z","timestamp":1715960110000},"source":"Crossref","is-referenced-by-count":3,"title":["Inhibition of mTORC1 by rapamycin results in feedback activation of Akt\n                  <sup>S473<\/sup>\n                  and aggravates hallmarks of osteoarthritis in female mice and non-human primates"],"prefix":"10.64898","author":[{"given":"Dennis M.","family":"Minton","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aditya R.","family":"Ailiani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael D.K.","family":"Focht","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariana E.","family":"Kersh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian J.","family":"Elliehausen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle M.","family":"Sonsalla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0079-4467","authenticated-orcid":false,"given":"Dudley W.","family":"Lamming","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela J.","family":"Marolf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly S","family":"Santangelo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam B.","family":"Salmon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam R.","family":"Konopka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025031105302056000_2024.05.14.594256v2.1","doi-asserted-by":"publisher","DOI":"10.1136\/rmdopen-2024-004164"},{"key":"2025031105302056000_2024.05.14.594256v2.2","doi-asserted-by":"publisher","DOI":"10.1038\/s43587-023-00416-y"},{"key":"2025031105302056000_2024.05.14.594256v2.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2022.02.024"},{"key":"2025031105302056000_2024.05.14.594256v2.4","doi-asserted-by":"publisher","DOI":"10.1186\/s13075-014-0482-4"},{"key":"2025031105302056000_2024.05.14.594256v2.5","doi-asserted-by":"publisher","DOI":"10.1038\/s41413-018-0036-5"},{"key":"2025031105302056000_2024.05.14.594256v2.6","doi-asserted-by":"crossref","unstructured":"Zhang H , Wang H , Zeng C , Yan B , Ouyang J , Liu X , et al. mTORC1 activation downregulates FGFR3 and PTH\/PTHrP receptor in articular chondrocytes to initiate osteoarthritis. 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