{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T21:42:06Z","timestamp":1783546926764,"version":"3.55.0"},"reference-count":43,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2025,8,14]],"date-time":"2025-08-14T00:00:00Z","timestamp":1755129600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["TA 1154\/1-1"],"award-info":[{"award-number":["TA 1154\/1-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["TA 1154\/1-2"],"award-info":[{"award-number":["TA 1154\/1-2"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["HE 5208\/2-1"],"award-info":[{"award-number":["HE 5208\/2-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["HE 5208\/2-3"],"award-info":[{"award-number":["HE 5208\/2-3"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["HE 5208\/3-1"],"award-info":[{"award-number":["HE 5208\/3-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002347","name":"Bundesministerium f\u00fcr Bildung und Forschung","doi-asserted-by":"publisher","award":["01KU1401B"],"award-info":[{"award-number":["01KU1401B"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Elsbeth Bonhoff Foundation","award":["83"],"award-info":[{"award-number":["83"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,10,28]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Bone remodeling is a dynamic process regulated by the activities of osteoclasts and osteoblasts. Imbalances in this process can lead to osteoporosis, a condition characterized by low bone mass and increased fracture risk. The homeodomain protein TG-interacting factor 1 (Tgif1) has been previously identified as a key regulator of osteoblast function. Here, we investigate the cell-autonomous role of Tgif1 in osteoclasts. Our findings reveal that Tgif1 is expressed in osteoclast precursors, with its expression increasing during RANKL and M-CSF-induced differentiation. Deletion of Tgif1 in the osteoclast lineage impairs osteoclast differentiation and resorption capacity, reducing aging-related bone loss in mice in vivo. Mechanistically, Tgif1 restricts ERK1\/2 dephosphorylation by suppressing protein phosphatase 2A (PP2A), an ERK1\/2 phosphatase. Inhibition of PP2A restores impaired differentiation of Tgif1-deficient osteoclasts, confirming its involvement in this process. These findings establish Tgif1 as an important regulator of osteoclast differentiation, function, and bone resorption, offering new insights into molecular mechanisms controlling bone mass maintenance.<\/jats:p>","DOI":"10.1093\/jbmr\/zjaf107","type":"journal-article","created":{"date-parts":[[2025,8,14]],"date-time":"2025-08-14T11:56:21Z","timestamp":1755172581000},"page":"1290-1305","source":"Crossref","is-referenced-by-count":2,"title":["Tgif1-deficiency impairs osteoclast differentiation through PP2A-mediated ERK1\/2 dephosphorylation and attenuates bone loss in mice"],"prefix":"10.1093","volume":"40","author":[{"given":"Miki","family":"Maeda","sequence":"first","affiliation":[{"name":"Molecular Skeletal Biology Laboratory, Department of Orthopedics and Trauma Surgery, University Medical Center Hamburg-Eppendorf , D-20251 Hamburg ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroaki","family":"Saito","sequence":"additional","affiliation":[{"name":"Molecular Skeletal Biology Laboratory, Department of Orthopedics and Trauma Surgery, University Medical Center Hamburg-Eppendorf , D-20251 Hamburg ,","place":["Germany"]},{"name":"Institute of Musculoskeletal Medicine, LMU University Hospital, LMU Munich , D-82152 Planegg-Martinsried ,","place":["Germany"]},{"name":"Musculoskeletal University Center Munich, LMU University Hospital, LMU Munich , D-82152 Planegg-Martinsried ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy B P","family":"Ribet","sequence":"additional","affiliation":[{"name":"Institute of Musculoskeletal Medicine, LMU University Hospital, LMU Munich , D-82152 Planegg-Martinsried ,","place":["Germany"]},{"name":"Musculoskeletal University Center Munich, LMU University Hospital, LMU Munich , D-82152 Planegg-Martinsried ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2778-7208","authenticated-orcid":false,"given":"Eric","family":"Hesse","sequence":"additional","affiliation":[{"name":"Molecular Skeletal Biology Laboratory, Department of Orthopedics and Trauma Surgery, University Medical Center Hamburg-Eppendorf , D-20251 Hamburg ,","place":["Germany"]},{"name":"Institute of Musculoskeletal Medicine, LMU University Hospital, LMU Munich , D-82152 Planegg-Martinsried ,","place":["Germany"]},{"name":"Musculoskeletal University Center Munich, LMU University Hospital, LMU Munich , D-82152 Planegg-Martinsried ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8254-9333","authenticated-orcid":false,"given":"Hanna","family":"Taipaleenm\u00e4ki","sequence":"additional","affiliation":[{"name":"Molecular Skeletal Biology Laboratory, Department of Orthopedics and Trauma Surgery, University Medical Center Hamburg-Eppendorf , D-20251 Hamburg ,","place":["Germany"]},{"name":"Institute of Musculoskeletal Medicine, LMU University Hospital, LMU Munich , D-82152 Planegg-Martinsried ,","place":["Germany"]},{"name":"Musculoskeletal University Center Munich, LMU University Hospital, LMU Munich , D-82152 Planegg-Martinsried ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,8,14]]},"reference":[{"issue":"2","key":"2025103115331992100_ref1","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1210\/jc.2011-2332","article-title":"Update on bone anabolics in osteoporosis treatment: rationale, current status, and perspectives","volume":"97","author":"Baron","year":"2012","journal-title":"J Clin Endocrinol Metab"},{"issue":"1","key":"2025103115331992100_ref2","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1196\/annals.1365.035","article-title":"Bone Remodeling","volume":"1092","author":"Hadjidakis","year":"2006","journal-title":"Ann N Y Acad Sci"},{"issue":"6937","key":"2025103115331992100_ref3","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1038\/nature01660","article-title":"Control of osteoblast function and regulation of bone mass","volume":"423","author":"Harada","year":"2003","journal-title":"Nature"},{"issue":"2 Suppl","key":"2025103115331992100_ref4","article-title":"Epidemiology, etiology, and diagnosis of osteoporosis","volume":"194","author":"Lane","year":"2006","journal-title":"Am J Obstet Gynecol"},{"issue":"3","key":"2025103115331992100_ref5","doi-asserted-by":"crossref","first-page":"171","DOI":"10.5312\/wjo.v7.i3.171","article-title":"Major osteoporotic fragility fractures: risk factor updates and societal impact","volume":"7","author":"Pisani","year":"2016","journal-title":"World J Orthop"},{"key":"2025103115331992100_ref6","doi-asserted-by":"crossref","first-page":"116538","DOI":"10.1016\/j.bone.2022.116538","article-title":"The origins and formation of bone-resorbing osteoclasts","volume":"164","author":"Elson","year":"2022","journal-title":"Bone"},{"key":"2025103115331992100_ref7","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1146\/annurev-pathmechdis-031521-040919","article-title":"Osteoclasts, master sculptors of bone","volume":"18","author":"Veis","year":"2024","journal-title":"Annu Rev Pathol"},{"issue":"1","key":"2025103115331992100_ref8","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1196\/annals.1346.014","article-title":"M-CSF, c-Fms, and signaling in osteoclasts and their precursors","volume":"1068","author":"Ross","year":"2006","journal-title":"Ann N Y Acad Sci"},{"issue":"2","key":"2025103115331992100_ref9","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1007\/s11154-014-9308-6","article-title":"RANKL\/OPG; critical role in bone physiology","volume":"16","author":"Martin","year":"2015","journal-title":"Rev Endocr Metab Disord"},{"issue":"4","key":"2025103115331992100_ref10","doi-asserted-by":"crossref","first-page":"233","DOI":"10.11005\/jbm.2014.21.4.233","article-title":"Regulation of NFATc1 in osteoclast differentiation","volume":"21","author":"Kim","year":"2014","journal-title":"J Bone Metab"},{"issue":"2","key":"2025103115331992100_ref11","doi-asserted-by":"crossref","first-page":"235","DOI":"10.7150\/ijbs.13814","article-title":"Selective regulation of MAPK signaling mediates RANKL-dependent osteoclast differentiation","volume":"12","author":"Lee","year":"2016","journal-title":"Int J Biol Sci"},{"issue":"12","key":"2025103115331992100_ref12","doi-asserted-by":"crossref","first-page":"2325","DOI":"10.1016\/j.cellsig.2015.09.002","article-title":"Insulin enhances RANKL-induced osteoclastogenesis via ERK1\/2 activation and induction of NFATc1 and Atp6v0d2","volume":"27","author":"Oh","year":"2015","journal-title":"Cell Signal"},{"issue":"1","key":"2025103115331992100_ref13","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3109\/s10165-003-0257-2","article-title":"Osteoclastic bone resorption through receptor tyrosine kinase and extracellular signal-regulated kinase signaling in mature osteoclasts","volume":"14","author":"Kawaguchi","year":"2004","journal-title":"Mod Rheumatol"},{"issue":"52","key":"2025103115331992100_ref14","doi-asserted-by":"crossref","first-page":"49343","DOI":"10.1074\/jbc.M103642200","article-title":"Tumor necrosis factor-\u03b1 supports the survival of osteoclasts through the activation of Akt and ERK","volume":"276","author":"Lee","year":"2001","journal-title":"J Biol Chem"},{"issue":"2","key":"2025103115331992100_ref15","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1210\/clinem\/dgad496","article-title":"Sequential therapy for the long-term treatment of postmenopausal osteoporosis","volume":"109","author":"Ramchand","year":"2024","journal-title":"J Clin Endocrinol Metab"},{"key":"2025103115331992100_ref16","first-page":"139","article-title":"Treatment of postmenopausal osteoporosis with bone-forming and antiresorptive treatments: combined and sequential approaches","author":"Langdahl","year":"2020","journal-title":"Bone"},{"issue":"7","key":"2025103115331992100_ref17","doi-asserted-by":"crossref","first-page":"777","DOI":"10.4158\/EP-2019-0596","article-title":"Anabolic therapy and optimal treatment sequences for patients with osteoporosis at high risk for fracture","volume":"26","author":"Cosman","year":"2020","journal-title":"Endocr Pract"},{"issue":"1","key":"2025103115331992100_ref18","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-019-08778-x","article-title":"TG-interacting factor 1 (Tgif1)-deficiency attenuates bone remodeling and blunts the anabolic response to parathyroid hormone","volume":"10","author":"Saito","year":"2019","journal-title":"Nat Commun"},{"key":"2025103115331992100_ref19","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.94265","article-title":"Tgif1-deficiency impairs cytoskeletal architecture in osteoblasts by activating PAK3 signaling","volume":"13","author":"Bolamperti","year":"2024","journal-title":"Elife"},{"issue":"1","key":"2025103115331992100_ref20","doi-asserted-by":"crossref","DOI":"10.1186\/s13058-020-01269-8","article-title":"Breast cancer bone metastases are attenuated in a Tgif1-deficient bone microenvironment","volume":"22","author":"Haider","year":"2020","journal-title":"Breast Cancer Res"},{"issue":"10","key":"2025103115331992100_ref21","doi-asserted-by":"crossref","DOI":"10.3390\/ijms19103004","article-title":"Roles of mitogen-activated protein kinases in osteoclast biology","volume":"19","author":"Lee","year":"2018","journal-title":"Int J Mol Sci"},{"issue":"9","key":"2025103115331992100_ref22","doi-asserted-by":"crossref","first-page":"3639","DOI":"10.1128\/MCB.25.9.3639-3647.2005","article-title":"Targeted disruption of Tgif, the mouse ortholog of a human holoprosencephaly gene, does not result in holoprosencephaly in mice","volume":"25","author":"Shen","year":"2005","journal-title":"Mol Cell Biol"},{"issue":"5","key":"2025103115331992100_ref23","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1016\/j.cell.2007.07.025","article-title":"Estrogen prevents bone loss via estrogen receptor \u03b1 and induction of Fas ligand in osteoclasts","volume":"130","author":"Nakamura","year":"2007","journal-title":"Cell."},{"issue":"4","key":"2025103115331992100_ref24","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1016\/j.bone.2007.05.018","article-title":"Automated compartmental analysis for high-throughput skeletal phenotyping in femora of genetic mouse models","volume":"41","author":"Kohler","year":"2007","journal-title":"Bone"},{"issue":"7","key":"2025103115331992100_ref25","doi-asserted-by":"crossref","first-page":"1468","DOI":"10.1002\/jbmr.141","article-title":"Guidelines for assessment of bone microstructure in rodents using micro-computed tomography","volume":"25","author":"Bouxsein","year":"2010","journal-title":"J Bone Miner Res"},{"issue":"6","key":"2025103115331992100_ref26","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1002\/jbmr.5650020617","article-title":"Bone histomorphometry: standardization of nomenclature, symbols, and units: report of the asbmr histomorphometry nomenclature committee","volume":"2","author":"Parfitt","year":"1987","journal-title":"J Bone Miner Res"},{"issue":"1","key":"2025103115331992100_ref27","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1002\/jbmr.1805","article-title":"Standardized nomenclature, symbols, and units for bone histomorphometry: a 2012 update of the report of the ASBMR histomorphometry nomenclature committee","volume":"28","author":"Dempster","year":"2013","journal-title":"J Bone Miner Res"},{"issue":"1","key":"2025103115331992100_ref28","doi-asserted-by":"crossref","DOI":"10.1002\/jbm4.10706","article-title":"Visualizing cathepsin K-Cre expression at the single-cell level with GFP reporters","volume":"7","author":"Chai","year":"2023","journal-title":"JBMR Plus"},{"issue":"2","key":"2025103115331992100_ref29","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.phrs.2012.04.005","article-title":"ERK1\/2 MAP kinases: structure, function, and regulation","volume":"66","author":"Roskoski","year":"2012","journal-title":"Pharmacol Res"},{"issue":"1","key":"2025103115331992100_ref30","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1007\/s11596-018-1854-9","article-title":"PP2A inhibits cervical cancer cell migration by dephosphorylation of p-JNK, p-p38 and the p-ERK\/MAPK Signaling pathway","volume":"38","author":"Zheng","year":"2018","journal-title":"Curr Med Sci"},{"issue":"6","key":"2025103115331992100_ref31","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1016\/j.cell.2006.11.033","article-title":"Structure of the protein phosphatase 2A holoenzyme","volume":"127","author":"Xu","year":"2006","journal-title":"Cell"},{"issue":"1","key":"2025103115331992100_ref32","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.canlet.2013.02.036","article-title":"Phosphatase: PP2A structural importance, regulation and its aberrant expression in cancer","volume":"335","author":"Seshacharyulu","year":"2013","journal-title":"Cancer Lett"},{"issue":"3","key":"2025103115331992100_ref33","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/0968-0004(90)90192-E","article-title":"Okadaic acid: a new probe for the study of cellular regulation","volume":"15","author":"Cohen","year":"1990","journal-title":"Trends Biochem Sci"},{"issue":"1","key":"2025103115331992100_ref34","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1101\/SQB.1988.053.01.060","article-title":"Macrophage colony-stimulating factor, CSF-1, and its proto-oncogene-encoded receptor","volume":"53","author":"Sherr","year":"1988","journal-title":"Cold Spring Harb Symp Quant Biol"},{"issue":"13","key":"2025103115331992100_ref35","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.1038\/sj.onc.1201518","article-title":"Identification of a second Grb2 binding site in the v-Fms tyrosine kinase","volume":"15","author":"Mancini","year":"1997","journal-title":"Oncogene"},{"issue":"2","key":"2025103115331992100_ref36","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/S0092-8674(00)81569-X","article-title":"Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation","volume":"93","author":"Lacey","year":"1998","journal-title":"Cell"},{"issue":"6717","key":"2025103115331992100_ref37","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1038\/16852","article-title":"OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis","volume":"397","author":"Kong","year":"1999","journal-title":"Nature"},{"issue":"1","key":"2025103115331992100_ref38","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.molmed.2005.11.007","article-title":"RANKL-RANK signaling in osteoclastogenesis and bone disease","volume":"12","author":"Wada","year":"2006","journal-title":"Trends Mol Med"},{"issue":"14","key":"2025103115331992100_ref39","doi-asserted-by":"crossref","first-page":"7829","DOI":"10.1073\/pnas.130200197","article-title":"Estrogens suppress RANK ligand-induced osteoclast differentiation via a stromal cell independent mechanism involving c-Jun repression","volume":"97","author":"Shevde","year":"2000","journal-title":"Proc Natl Acad Sci USA"},{"issue":"12","key":"2025103115331992100_ref40","doi-asserted-by":"crossref","first-page":"8836","DOI":"10.1074\/jbc.M010764200","article-title":"Estrogen decreases osteoclast formation by down-regulating receptor activator of NF-\u03baB ligand (RANKL)-induced JNK activation","volume":"276","author":"Srivastava","year":"2001","journal-title":"J Biol Chem"},{"issue":"32","key":"2025103115331992100_ref41","doi-asserted-by":"crossref","first-page":"2643","DOI":"10.2174\/1381612033453640","article-title":"New insights into the molecular mechanisms of action of bisphosphonates","volume":"9","author":"Rogers","year":"2005","journal-title":"Curr Pharm Des"},{"issue":"1","key":"2025103115331992100_ref42","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1423-0127-21-10","article-title":"Nitrogen-containing bisphosphonates inhibit RANKL- and M-CSF-induced osteoclast formation through the inhibition of ERK1\/2 and Akt activation","volume":"21","author":"Tsubaki","year":"2014","journal-title":"J Biomed Sci"},{"issue":"8","key":"2025103115331992100_ref43","doi-asserted-by":"crossref","first-page":"1301","DOI":"10.1359\/jbmr.070501","article-title":"Toll-like receptor 9 ligand blocks osteoclast differentiation through induction of phosphatase","volume":"22","author":"Amcheslavsky","year":"2007","journal-title":"J Bone Miner Res"}],"container-title":["Journal of Bone and Mineral Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jbmr\/advance-article-pdf\/doi\/10.1093\/jbmr\/zjaf107\/64044148\/zjaf107.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/40\/11\/1290\/64044148\/zjaf107.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/40\/11\/1290\/64044148\/zjaf107.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T19:33:26Z","timestamp":1761939206000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jbmr\/article\/40\/11\/1290\/8234318"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,14]]},"references-count":43,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2025,8,14]]},"published-print":{"date-parts":[[2025,10,28]]}},"URL":"https:\/\/doi.org\/10.1093\/jbmr\/zjaf107","relation":{},"ISSN":["0884-0431","1523-4681"],"issn-type":[{"value":"0884-0431","type":"print"},{"value":"1523-4681","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,11]]},"published":{"date-parts":[[2025,8,14]]}}}