{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T15:26:22Z","timestamp":1789053982531,"version":"build-2803163510"},"reference-count":37,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2021,2,20]],"date-time":"2021-02-20T00:00:00Z","timestamp":1613779200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Paired box protein 5 (Pax5) is a crucial transcription factor responsible for B-cell lineage specification and commitment. In this study, we identified a negative role of Pax5 in osteoclastogenesis. The expression of Pax5 was time-dependently downregulated by receptor activator of nuclear factor kappa B (RANK) ligand (RANKL) stimulation in osteoclastogenesis. Osteoclast (OC) differentiation and bone resorption were inhibited (68.9% and 48% reductions, respectively) by forced expression of Pax5 in OC lineage cells. Pax5 led to the induction of antiosteoclastogenic factors through downregulation of B lymphocyte-induced maturation protein 1 (Blimp1). To examine the negative role of Pax5 in vivo, we generated Pax5 transgenic (Pax5Tg) mice expressing the human Pax5 transgene under the control of the tartrate-resistant acid phosphatase (TRAP) promoter, which is expressed mainly in OC lineage cells. OC differentiation and bone resorption were inhibited (54.2\u201376.9% and 24.0\u201326.2% reductions, respectively) in Pax5Tg mice, thereby contributing to the osteopetrotic-like bone phenotype characterized by increased bone mineral density (13.0\u201313.6% higher), trabecular bone volume fraction (32.5\u201338.1% higher), trabecular thickness (8.4\u20139.0% higher), and trabecular number (25.5\u201326.7% higher) and decreased trabecular spacing (9.3\u201310.4% lower) compared to wild-type control mice. Furthermore, the number of OCs was decreased (48.8\u201365.3% reduction) in Pax5Tg mice. These findings indicate that Pax5 plays a negative role in OC lineage specification and commitment through Blimp1 downregulation. Thus, our data suggest that the Pax5\u2013Blimp1 axis is crucial for the regulation of RANKL-induced osteoclastogenesis.<\/jats:p>","DOI":"10.3390\/ijms22042097","type":"journal-article","created":{"date-parts":[[2021,2,21]],"date-time":"2021-02-21T21:15:01Z","timestamp":1613942101000},"page":"2097","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Pax5 Negatively Regulates Osteoclastogenesis through Downregulation of Blimp1"],"prefix":"10.3390","volume":"22","author":[{"given":"Jiyeon","family":"Yu","sequence":"first","affiliation":[{"name":"Department of Microbiology and Molecular Biology, College of Bioscience and Biotechnology, Chungnam National University, Daejeon 34134, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sumi","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Biology, College of Bioscience and Biotechnology, Chungnam National University, Daejeon 34134, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nari","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Biology, College of Bioscience and Biotechnology, Chungnam National University, Daejeon 34134, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyoeun","family":"Jeon","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Biology, College of Bioscience and Biotechnology, Chungnam National University, Daejeon 34134, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery, School of Dentistry, College of Dentistry, Wonkwang University, Iksan 54538, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4506-3975","authenticated-orcid":false,"given":"Masamichi","family":"Takami","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Dentistry, Showa University, 1-5-8 Hatanodai, Shinagawaku 142-8555, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0019-4939","authenticated-orcid":false,"given":"Jaerang","family":"Rho","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Biology, College of Bioscience and Biotechnology, Chungnam National University, Daejeon 34134, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,2,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e8","DOI":"10.4110\/in.2018.18.e8","article-title":"Regulation of Osteoclast Differentiation by Cytokine Networks","volume":"18","author":"Amarasekara","year":"2018","journal-title":"Immune Netw."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1146\/annurev.immunol.24.021605.090646","article-title":"Osteoimmunology: Interplay between the immune system and bone metabolism","volume":"24","author":"Walsh","year":"2006","journal-title":"Annu. Rev. Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"832127","DOI":"10.1155\/2015\/832127","article-title":"Bone Loss Triggered by the Cytokine Network in Inflammatory Autoimmune Diseases","volume":"2015","author":"Amarasekara","year":"2015","journal-title":"J. Immunol. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S1016-8478(23)12997-9","article-title":"Osteoimmunology: Interactions of the immune and skeletal systems","volume":"17","author":"Rho","year":"2004","journal-title":"Mol. Cells"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1084\/jem.20091957","article-title":"The Blimp1-Bcl6 axis is critical to regulate osteoclast differentiation and bone homeostasis","volume":"207","author":"Miyauchi","year":"2010","journal-title":"J. Exp. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1038\/nri2062","article-title":"Osteoimmunology: Shared mechanisms and crosstalk between the immune and bone systems","volume":"7","author":"Takayanagi","year":"2007","journal-title":"Nat. Rev. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1038\/ni1454","article-title":"Pax5: The guardian of B cell identity and function","volume":"8","author":"Cobaleda","year":"2007","journal-title":"Nat. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1101\/gad.6.9.1589","article-title":"Pax-5 encodes the transcription factor BSAP and is expressed in B lymphocytes, the developing CNS, and adult testis","volume":"6","author":"Adams","year":"1992","journal-title":"Genes Dev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1016\/S1074-7613(00)80268-X","article-title":"Identification of the earliest B lineage stage in mouse bone marrow","volume":"5","author":"Li","year":"1996","journal-title":"Immunity"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"4771","DOI":"10.1128\/MCB.22.13.4771-4780.2002","article-title":"Blimp-1-dependent repression of Pax-5 is required for differentiation of B cells to immunoglobulin M-secreting plasma cells","volume":"22","author":"Lin","year":"2002","journal-title":"Mol. Cell Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3150","DOI":"10.1182\/blood-2007-05-092262","article-title":"Human BSAP and BLIMP1 conform an autoregulatory feedback loop","volume":"110","author":"Reales","year":"2007","journal-title":"Blood"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1016\/S1074-7613(03)00267-X","article-title":"Blimp-1 is required for the formation of immunoglobulin secreting plasma cells and pre-plasma memory B cells","volume":"19","author":"Lin","year":"2003","journal-title":"Immunity"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/j.immuni.2006.02.003","article-title":"Loss of Pax5 promotes plasma cell differentiation","volume":"24","author":"Nera","year":"2006","journal-title":"Immunity"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1038\/44076","article-title":"Commitment to the B-lymphoid lineage depends on the transcription factor Pax5","volume":"401","author":"Nutt","year":"1999","journal-title":"Nature"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"6583","DOI":"10.4049\/jimmunol.173.11.6583","article-title":"Pax5-deficient mice exhibit early onset osteopenia with increased osteoclast progenitors","volume":"173","author":"Horowitz","year":"2004","journal-title":"J. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1002\/gene.20041","article-title":"Transgenic mice that express Cre recombinase in osteoclasts","volume":"39","author":"Chiu","year":"2004","journal-title":"Genesis"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1016\/j.immuni.2007.05.010","article-title":"The transcriptional regulation of B cell lineage commitment","volume":"26","author":"Nutt","year":"2007","journal-title":"Immunity"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"4342","DOI":"10.1182\/blood-2002-10-3139","article-title":"Pax5 determines B- versus T-cell fate and does not block early myeloid-lineage development","volume":"101","author":"Cotta","year":"2003","journal-title":"Blood"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"R933","DOI":"10.1016\/S0960-9822(00)80108-6","article-title":"B-cell commitment: Pax5 is the deciding factor","volume":"9","author":"Enver","year":"1999","journal-title":"Curr. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1016\/0092-8674(95)90518-9","article-title":"Crystal structure of a paired domain-DNA complex at 2.5 A resolution reveals structural basis for Pax developmental mutations","volume":"80","author":"Xu","year":"1995","journal-title":"Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1267","DOI":"10.1016\/S1097-2765(01)00410-5","article-title":"Structural studies of Ets-1\/Pax5 complex formation on DNA","volume":"8","author":"Garvie","year":"2001","journal-title":"Mol. Cell"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2048","DOI":"10.1101\/gad.7.10.2048","article-title":"DNA sequence recognition by Pax proteins: Bipartite structure of the paired domain and its binding site","volume":"7","author":"Czerny","year":"1993","journal-title":"Genes Dev."},{"key":"ref_23","first-page":"2662","article-title":"The promoter of the CD19 gene is a target for the B-cell-specific transcription factor BSAP","volume":"12","author":"Kozmik","year":"1992","journal-title":"Mol. Cell Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1971","DOI":"10.1002\/j.1460-2075.1996.tb00548.x","article-title":"C-terminal activating and inhibitory domains determine the transactivation potential of BSAP (Pax-5), Pax-2 and Pax-8","volume":"15","author":"Dorfler","year":"1996","journal-title":"EMBO J."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2292","DOI":"10.1093\/emboj\/19.10.2292","article-title":"Transcriptional repression by Pax5 (BSAP) through interaction with corepressors of the Groucho family","volume":"19","author":"Eberhard","year":"2000","journal-title":"EMBO J."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"24671","DOI":"10.1074\/jbc.274.35.24671","article-title":"AML1 (CBFalpha2) cooperates with B cell-specific activating protein (BSAP\/PAX5) in activation of the B cell-specific BLK gene promoter","volume":"274","author":"Libermann","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1911","DOI":"10.1128\/MCB.20.6.1911-1922.2000","article-title":"BSAP can repress enhancer activity by targeting PU.1 function","volume":"20","author":"Maitra","year":"2000","journal-title":"Mol. Cell Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1210\/me.2013-1305","article-title":"Runx1-mediated regulation of osteoclast differentiation and function","volume":"28","author":"Soung","year":"2014","journal-title":"Mol. Endocrinol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1038\/386081a0","article-title":"Osteopetrosis in mice lacking haematopoietic transcription factor PU.1","volume":"386","author":"Tondravi","year":"1997","journal-title":"Nature"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3117","DOI":"10.1073\/pnas.0912779107","article-title":"Blimp1-mediated repression of negative regulators is required for osteoclast differentiation","volume":"107","author":"Nishikawa","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.1038\/nm1514","article-title":"v-ATPase V0 subunit d2-deficient mice exhibit impaired osteoclast fusion and increased bone formation","volume":"12","author":"Lee","year":"2006","journal-title":"Nat. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"35868","DOI":"10.1074\/jbc.M114.589614","article-title":"Secretion of a truncated osteopetrosis-associated transmembrane protein 1 (OSTM1) mutant inhibits osteoclastogenesis through down-regulation of the B lymphocyte-induced maturation protein 1 (BLIMP1)-nuclear factor of activated T cells c1 (NFATc1) axis","volume":"289","author":"Shin","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"9660","DOI":"10.1074\/jbc.M114.609685","article-title":"Tumor necrosis factor (TNF) receptor-associated factor (TRAF)-interacting protein (TRIP) negatively regulates the TRAF2 ubiquitin-dependent pathway by suppressing the TRAF2-sphingosine 1-phosphate (S1P) interaction","volume":"290","author":"Park","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"20643","DOI":"10.1074\/jbc.M116.728303","article-title":"Interaction of Tumor Necrosis Factor Receptor-associated Factor 6 (TRAF6) and Vav3 in the Receptor Activator of Nuclear Factor kappaB (RANK) Signaling Complex Enhances Osteoclastogenesis","volume":"291","author":"Yu","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Yun, H., Park, E.S., Choi, S., Shin, B., Yu, J., Yu, J., Amarasekara, D.S., Kim, S., Lee, N., and Choi, J.S. (2019). TDAG51 is a crucial regulator of maternal care and depressive-like behavior after parturition. PLoS Genet, 15.","DOI":"10.1371\/journal.pgen.1008214"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1","DOI":"10.14348\/molcells.2020.0143","article-title":"T-Cell Death Associated Gene 51 Is a Novel Negative Regulator of PPARgamma That Inhibits PPARgammaRXRalpha Heterodimer Formation in Adipogenesis","volume":"44","author":"Kim","year":"2020","journal-title":"Mol. Cells"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.bbrc.2010.10.117","article-title":"ATP6v0d2 deficiency increases bone mass, but does not influence ovariectomy-induced bone loss","volume":"403","author":"Kim","year":"2010","journal-title":"Biochem. Biophys. Res. Commun."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/4\/2097\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:26:51Z","timestamp":1760160411000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/4\/2097"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,20]]},"references-count":37,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,2]]}},"alternative-id":["ijms22042097"],"URL":"https:\/\/doi.org\/10.3390\/ijms22042097","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,20]]}}}