{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T11:50:58Z","timestamp":1789559458922,"version":"build-2803163510"},"reference-count":52,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"940","funder":[{"DOI":"10.13039\/100019769","name":"FP7 People","doi-asserted-by":"publisher","award":["R01GM57603"],"award-info":[{"award-number":["R01GM57603"]}],"id":[{"id":"10.13039\/100019769","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100019769","name":"FP7 People","doi-asserted-by":"publisher","award":["81870620"],"award-info":[{"award-number":["81870620"]}],"id":[{"id":"10.13039\/100019769","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100019769","name":"FP7 People","doi-asserted-by":"publisher","award":["2024NSFSC0675"],"award-info":[{"award-number":["2024NSFSC0675"]}],"id":[{"id":"10.13039\/100019769","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100019769","name":"FP7 People","doi-asserted-by":"publisher","award":["2022CFB281"],"award-info":[{"award-number":["2022CFB281"]}],"id":[{"id":"10.13039\/100019769","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81870620"],"award-info":[{"award-number":["81870620"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003819","name":"Natural Science Foundation of Hubei Province","doi-asserted-by":"publisher","award":["2022CFB281"],"award-info":[{"award-number":["2022CFB281"]}],"id":[{"id":"10.13039\/501100003819","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100018542","name":"Natural Science Foundation of Sichuan Province","doi-asserted-by":"publisher","award":["2024NSFSC0675"],"award-info":[{"award-number":["2024NSFSC0675"]}],"id":[{"id":"10.13039\/501100018542","id-type":"DOI","asserted-by":"publisher"}]},{"name":"XZ the Sichuan Science and Technology Program","award":["2024NSFSC0675"],"award-info":[{"award-number":["2024NSFSC0675"]}]}],"content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Signal."],"published-print":{"date-parts":[[2026,6,2]]},"abstract":"<jats:p>\n                    Osteoarthritis (OA) is a common chronic joint disease with limited treatment options. Cartilage degeneration in OA is driven by increased matrix catabolism and decreased matrix production and is characterized by chondrocyte hypertrophy. Aberrant activation of both \u03b2-catenin\u2013dependent and \u03b2-catenin\u2013independent Wnt signaling is implicated in OA progression and represents a potential therapeutic target. Here, we investigated the role of Tiki2, a membrane-tethered proteolytic inhibitor of Wnt ligands, in OA. Expression of\n                    <jats:italic toggle=\"yes\">Tiki2<\/jats:italic>\n                    was reduced in a mouse model of OA induced by joint destabilization, and expression of\n                    <jats:italic toggle=\"yes\">TIKI2<\/jats:italic>\n                    was reduced across multiple independent human OA transcriptomic datasets.\n                    <jats:italic toggle=\"yes\">Tiki2<\/jats:italic>\n                    haploinsufficiency in mice led to spontaneous cartilage degeneration, and loss of\n                    <jats:italic toggle=\"yes\">Tiki2<\/jats:italic>\n                    accelerated the progression of instability-induced OA. Tiki2 suppressed Wnt3a-induced \u03b2-catenin signaling and Wnt5a-induced \u03b2-catenin\u2013independent signaling in chondrocytes and promoted anabolic gene expression to preserve cartilage integrity. Intra-articular overexpression of human TIKI2 attenuated OA-associated cartilage degeneration in mice. In vitro, Tiki2 inhibited hypertrophic differentiation in primary mouse chondrocytes and ATDC5 cells, and overexpression of TIKI2 promoted chondrogenic differentiation in primary mouse and human chondrocytes. Together, these results identify Tiki2 as a regulator of articular cartilage homeostasis and OA susceptibility and suggest that enhancing Tiki2-mediated Wnt inhibition may be a potential disease-modifying strategy for OA.\n                  <\/jats:p>","DOI":"10.1126\/scisignal.adv0789","type":"journal-article","created":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T17:58:26Z","timestamp":1780423106000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":2,"title":["The Wnt inhibitor Tiki2 maintains articular cartilage homeostasis and protects against osteoarthritis"],"prefix":"10.1126","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-7730-5918","authenticated-orcid":true,"given":"Xuemei","family":"Li","sequence":"first","affiliation":[{"name":"Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China."},{"name":"Genetic Diseases Key Laboratory of Sichuan Province and Department of Laboratory Medicine, Sichuan Provincial People\u2019s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-1154-3111","authenticated-orcid":true,"given":"Weiwei","family":"Zhao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2090-2066","authenticated-orcid":true,"given":"Bryan T.","family":"MacDonald","sequence":"additional","affiliation":[{"name":"F. M. Kirby Neurobiology Center, Boston Children\u2019s Hospital, Department of Neurology, Harvard Medical School, Boston, MA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9938-4179","authenticated-orcid":true,"given":"Hengye","family":"Zhang","sequence":"additional","affiliation":[{"name":"Genetic Diseases Key Laboratory of Sichuan Province and Department of Laboratory Medicine, Sichuan Provincial People\u2019s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-3217-2433","authenticated-orcid":true,"given":"Wenqi","family":"Duan","sequence":"additional","affiliation":[{"name":"Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2971-3034","authenticated-orcid":true,"given":"Kai","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8093-7981","authenticated-orcid":true,"given":"Xi","family":"He","sequence":"additional","affiliation":[{"name":"F. M. Kirby Neurobiology Center, Boston Children\u2019s Hospital, Department of Neurology, Harvard Medical School, Boston, MA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2409-4104","authenticated-orcid":true,"given":"Xinjun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Genetic Diseases Key Laboratory of Sichuan Province and Department of Laboratory Medicine, Sichuan Provincial People\u2019s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China."},{"name":"Research Unit for Blindness Prevention of the Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People\u2019s Hospital, Chengdu, China."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(19)30417-9"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-023-01330-w"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.2147\/DDDT.S295224"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1177\/23259671231155950"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2010.198"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2016-210407"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-12910-2"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2011.12.003"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21072358"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms10959"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1007\/164_2021_525"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.berh.2018.03.004"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1111\/cpr.13600"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1111\/iep.12472"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.05.016"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.23614"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1359\/jbmr.080901"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2009.081173"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.23137"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0403456101"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.21673"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aax3063"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2015-208577"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201011051"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.04.039"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M115.677807"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1387\/ijdb.140106ja"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.15252\/embr.202255873"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1002\/1873-3468.14320"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2018.07.012"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2021-220000"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1407679"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2010.196"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1002\/dvdy.20892"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1111\/nyas.13930"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41413-021-00179-5"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-10753-5"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.24467"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2004.03.004"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2012.06.016"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13287-020-02026-6"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1359\/jbmr.1997.12.8.1174"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.34535"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1186\/ar2029"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.41315"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2019.07.023"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.sbi.2014.10.003"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.4103\/0976-500X.119726"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2007.03.006"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2010.05.025"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.41552"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2008.95"}],"container-title":["Science Signaling"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/scisignal.adv0789","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T17:58:31Z","timestamp":1780423111000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/scisignal.adv0789"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,2]]},"references-count":52,"journal-issue":{"issue":"940","published-print":{"date-parts":[[2026,6,2]]}},"alternative-id":["10.1126\/scisignal.adv0789"],"URL":"https:\/\/doi.org\/10.1126\/scisignal.adv0789","relation":{},"ISSN":["1945-0877","1937-9145"],"issn-type":[{"value":"1945-0877","type":"print"},{"value":"1937-9145","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,2]]},"assertion":[{"value":"2024-12-04","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-09-29","order":1,"name":"revised","label":"Revised","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-06","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-02","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eadv0789"}}