{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T03:34:25Z","timestamp":1788838465964,"version":"build-2803163510"},"reference-count":47,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"33","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2022,8,19]]},"abstract":"<jats:p>\n            Ectopic endochondral ossification in the tendon\/ligament is caused by repetitive mechanical overload or inflammation. Tendon stem\/progenitor cells (TSPCs) contribute to tissue repair, and some express lubricin [proteoglycan 4 (PRG4)]. However, the mechanisms of ectopic ossification and association of TSPCs are not yet known. Here, we investigated the characteristics of Prg4-positive (\n            <jats:sup>+<\/jats:sup>\n            ) cells and identified that R-spondin 2 (RSPO2), a WNT activator, is specifically expressed in a distinct\n            <jats:italic>\n              Prg4\n              <jats:sup>+<\/jats:sup>\n            <\/jats:italic>\n            TSPC cluster. The\n            <jats:italic>Rspo2<\/jats:italic>\n            <jats:sup>+<\/jats:sup>\n            cluster was characterized as mostly undifferentiated, and RSPO2 overexpression suppressed ectopic ossification in a mouse Achilles tendon puncture model via chondrogenic differentiation suppression.\n            <jats:italic>RSPO2<\/jats:italic>\n            expression levels in patients with ossification of the posterior longitudinal ligament were lower than those in spondylosis patients, and RSPO2 protein suppressed chondrogenic differentiation of human ligament cells. RSPO2 was induced by inflammatory stimulation and mechanical loading via nuclear factor \u03baB.\n            <jats:italic>\n              Rspo2\n              <jats:sup>+<\/jats:sup>\n            <\/jats:italic>\n            cells may contribute to tendon\/ligament homeostasis under pathogenic conditions.\n          <\/jats:p>","DOI":"10.1126\/sciadv.abn2138","type":"journal-article","created":{"date-parts":[[2022,8,19]],"date-time":"2022-08-19T17:57:37Z","timestamp":1660931857000},"source":"Crossref","is-referenced-by-count":50,"title":["RSPO2 defines a distinct undifferentiated progenitor in the tendon\/ligament and suppresses ectopic ossification"],"prefix":"10.1126","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1073-5823","authenticated-orcid":true,"given":"Naohiro","family":"Tachibana","sequence":"first","affiliation":[{"name":"Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3125-4818","authenticated-orcid":true,"given":"Ryota","family":"Chijimatsu","sequence":"additional","affiliation":[{"name":"Bone and Cartilage Regenerative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Okada","sequence":"additional","affiliation":[{"name":"Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8009-1648","authenticated-orcid":true,"given":"Takeshi","family":"Oichi","sequence":"additional","affiliation":[{"name":"Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2329-123X","authenticated-orcid":true,"given":"Yuki","family":"Taniguchi","sequence":"additional","affiliation":[{"name":"Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuji","family":"Maenohara","sequence":"additional","affiliation":[{"name":"Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6369-5829","authenticated-orcid":true,"given":"Junya","family":"Miyahara","sequence":"additional","affiliation":[{"name":"Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6317-6087","authenticated-orcid":true,"given":"Hisatoshi","family":"Ishikura","sequence":"additional","affiliation":[{"name":"Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuhide","family":"Iwanaga","sequence":"additional","affiliation":[{"name":"Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan."},{"name":"Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusuke","family":"Arino","sequence":"additional","affiliation":[{"name":"Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4495-1134","authenticated-orcid":true,"given":"Kosei","family":"Nagata","sequence":"additional","affiliation":[{"name":"Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6929-9619","authenticated-orcid":true,"given":"Hideki","family":"Nakamoto","sequence":"additional","affiliation":[{"name":"Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0835-2724","authenticated-orcid":true,"given":"So","family":"Kato","sequence":"additional","affiliation":[{"name":"Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toru","family":"Doi","sequence":"additional","affiliation":[{"name":"Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2087-5774","authenticated-orcid":true,"given":"Yoshitaka","family":"Matsubayashi","sequence":"additional","affiliation":[{"name":"Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4696-1846","authenticated-orcid":true,"given":"Yasushi","family":"Oshima","sequence":"additional","affiliation":[{"name":"Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asuka","family":"Terashima","sequence":"additional","affiliation":[{"name":"Bone and Cartilage Regenerative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8912-7483","authenticated-orcid":true,"given":"Yasunori","family":"Omata","sequence":"additional","affiliation":[{"name":"Bone and Cartilage Regenerative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fumiko","family":"Yano","sequence":"additional","affiliation":[{"name":"Bone and Cartilage Regenerative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2737-3902","authenticated-orcid":true,"given":"Shingo","family":"Maeda","sequence":"additional","affiliation":[{"name":"Department of Bone and Joint Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiro","family":"Ikegawa","sequence":"additional","affiliation":[{"name":"Laboratory for Bone and Joint Diseases, Center for Integrative Medical Sciences, RIKEN, Tokyo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6091-8698","authenticated-orcid":true,"given":"Masahide","family":"Seki","sequence":"additional","affiliation":[{"name":"Laboratory of Systems Genomics, Department of Computational Biology and Medical Sciences, The University of Tokyo, Kashiwa, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutaka","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Laboratory of Systems Genomics, Department of Computational Biology and Medical Sciences, The University of Tokyo, Kashiwa, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9210-9414","authenticated-orcid":true,"given":"Sakae","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4911-3930","authenticated-orcid":true,"given":"Taku","family":"Saito","sequence":"additional","affiliation":[{"name":"Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.186916"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.15240"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0720-048X(97)00164-2"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3045"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2016.03.089"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1002\/jor.24156"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-019-0417-z"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200522263"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1002\/jor.21247"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/15496"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.39030"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.4226"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-02988-5"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-14172-4"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.04.048"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aax0249"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.e08-02-0187"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/labinvest.2015.142"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2016.05.018"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1002\/pmic.201900025"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1089\/scd.2016.0319"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.02.048"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature17997"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41413-021-00163-z"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.30474"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.13137"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.3389\/fbioe.2019.00038"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80257-3"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80258-5"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80259-7"},{"key":"e_1_3_3_32_2","first-page":"100141","article-title":"clusterProfiler 4.0: A universal enrichment tool for interpreting omics data","volume":"2","author":"Wu T.","year":"2021","unstructured":"T. Wu, E. Hu, S. Xu, M. Chen, P. Guo, Z. Dai, T. Feng, L. Zhou, W. Tang, L. Zhan, X. Fu, S. Liu, X. Bo, G. Yu, clusterProfiler 4.0: A universal enrichment tool for interpreting omics data. Innovation 2, 100141 (2021).","journal-title":"Innovation"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btv715"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.4402"},{"key":"e_1_3_3_35_2","doi-asserted-by":"crossref","unstructured":"K. Tsuyuzaki M. Ishii I. Nikaido Uncovering hypergraphs of cell-cell interaction from single cell RNA-sequencing data. bioRxiv 566182 (2019).","DOI":"10.1101\/566182"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2018.11.005"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-020-01520-0"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.4463"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aan0746"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-021-01857-0"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-09491-5"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M414275200"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1002\/dvdy.21865"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature22313"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-39393-x"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2018-213450"},{"key":"e_1_3_3_47_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13075-019-2041-5"},{"key":"e_1_3_3_48_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2020.115609"}],"container-title":["Science Advances"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/sciadv.abn2138","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,9]],"date-time":"2024-01-09T22:41:05Z","timestamp":1704840065000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/sciadv.abn2138"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,19]]},"references-count":47,"journal-issue":{"issue":"33","published-print":{"date-parts":[[2022,8,19]]}},"alternative-id":["10.1126\/sciadv.abn2138"],"URL":"https:\/\/doi.org\/10.1126\/sciadv.abn2138","relation":{},"ISSN":["2375-2548"],"issn-type":[{"value":"2375-2548","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,19]]},"article-number":"eabn2138"}}