{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T04:26:47Z","timestamp":1793680007097,"version":"4.5.1"},"reference-count":68,"publisher":"SAGE Publications","issue":"4","license":[{"start":{"date-parts":[[2025,11,7]],"date-time":"2025-11-07T00:00:00Z","timestamp":1762473600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2025,11,7]],"date-time":"2025-11-07T00:00:00Z","timestamp":1762473600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["CARTILAGE"],"published-print":{"date-parts":[[2026,12]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>This study investigates the molecular mechanism by which leucine (Leu) ameliorates collagenase-induced osteoarthritis (CIOA) through macrophage polarization regulation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A CIOA mouse model was established and evaluated by micro-computed tomography (micro-CT) and histopathological analysis. Leu intervention was administered, and its therapeutic effects on cartilage degeneration and osteophyte formation were assessed. Integrated multi-omics analyses and mechanistic assays were performed to explore the role of the mTORC1\/LXR\u03b1 pathway in synovial macrophage reprogramming and its regulation of the Rspo2\/\u03b2-catenin axis in chondroprogenitors. Functional validation was conducted using the LXR\u03b1 inhibitor GSK2033.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Leu intervention demonstrated significant therapeutic effects, reducing cartilage degeneration by 42% (Osteoarthritis Research Society International [OARSI] score) and osteophyte formation by 58% (volume reduction). Integrated multi-omics and mechanistic assays indicated that Leu activated mTORC1\/LXR\u03b1 to reprogram synovial macrophages toward an M2-like state, suppressed Rspo2, and attenuated \u03b2-catenin signaling in chondroprogenitors, thereby improving cartilage function. Functional validation using LXR\u03b1 inhibitor GSK2033 confirmed pathway specificity, reversing Leu-mediated cartilage protection and reactivating osteogenic differentiation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These findings establish a novel \u201cmetabolism-immunity-cartilage\u201d axis in which Leu coordinates mTORC1\/LXR\u03b1-driven macrophage reprogramming with Rspo2\/\u03b2-catenin axis suppression, offering dual-target therapeutic potential for osteoarthritis. The study redefines nutritional amino acids as immunometabolic modulators in degenerative joint diseases, proposing Leu supplementation as a viable strategy for interrupting the inflammation-bone remodeling cycle in traumatic arthritis. No clinical trials were involved in this preclinical investigation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/19476035251389178","type":"journal-article","created":{"date-parts":[[2025,11,7]],"date-time":"2025-11-07T09:46:23Z","timestamp":1762508783000},"page":"1059-1079","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":3,"title":["Leucine Attenuates Osteoarthritis via mTORC1\/LXR\u03b1-Mediated Macrophage Reprogramming and Rspo2\/\u03b2-Catenin Axis Suppression"],"prefix":"10.1177","volume":"17","author":[{"given":"Ke","family":"Zheng","sequence":"first","affiliation":[{"name":"Department of Orthopedics, The First Affiliated Hospital of Anhui Medical University, Hefei, China"},{"name":"Department of Orthopedics, Anhui No.2 Provincial People\u2019s Hospital, Hefei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiebin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Anhui No.2 Provincial People\u2019s Hospital, Hefei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenxiang","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Anhui No.2 Provincial People\u2019s Hospital, Hefei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-4945-8931","authenticated-orcid":false,"given":"Bin","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, The First Affiliated Hospital of Anhui Medical University, Hefei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2025,11,7]]},"reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-025-93124-z"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10067-025-07347-6"},{"issue":"9","key":"e_1_3_2_4_2","article-title":"Global, regional, and national burden of osteoarthritis, 1990\u20132020 and projections to 2050: a systematic analysis for the global burden of disease study 2021","volume":"5","author":"GBD 2021 Osteoarthritis Collaborators","year":"2023","unstructured":"GBD 2021 Osteoarthritis Collaborators. 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