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NF\u2010\u03baB signaling fundamentally influences the fate of bone\u2010forming osteoblasts and bone\u2010resorbing osteoclasts, but the role of BCL3 in bone biology has not been investigated. The objective of this study was to evaluate BCL3 in skeletal development, maintenance, and osteoarthritic pathology.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>To assess the contribution of BCL3 to skeletal homeostasis, neonatal mice (n\u00a0=\u00a06\u201314) lacking BCL3 (<jats:italic>Bcl3<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup>) and wild\u2010type (WT) controls were characterized for bone phenotype and density. To reveal the contribution to bone phenotype by the osteoblast compartment in <jats:italic>Bcl3<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice, transcriptomic analysis of early osteogenic differentiation and cellular function (n\u00a0=\u00a03\u20137) were assessed. Osteoclast differentiation and function in <jats:italic>Bcl3<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice (n\u00a0=\u00a03\u20135) was assessed. Adult 20\u2010week <jats:italic>Bcl3<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> and WT mice bone phenotype, strength, and turnover were assessed. A destabilization of the medial meniscus model of osteoarthritic osteophytogenesis was used to understand adult bone formation in <jats:italic>Bcl3<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice (n\u00a0=\u00a011\u201313).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Evaluation of <jats:italic>Bcl3<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice revealed congenitally increased bone density, long bone dwarfism, increased bone biomechanical strength, and altered bone turnover. Molecular and cellular characterization of mesenchymal precursors showed that <jats:italic>Bcl3<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> cells displayed an accelerated osteogenic transcriptional profile that led to enhanced differentiation into osteoblasts with increased functional activity, which could be reversed with a mimetic peptide. In a model of osteoarthritis\u2010induced osteophytogenesis, <jats:italic>Bcl3<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice exhibited decreased pathological osteophyte formation (<jats:italic>P<\/jats:italic> &lt;\u20090.05).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Cumulatively, these findings demonstrate that BCL3 controls developmental mineralization to enable appropriate bone formation, whereas in a pathological setting, it contributes to skeletal pathology.<\/jats:p><jats:p><jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/art42639-toc-0001-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><\/jats:sec>","DOI":"10.1002\/art.42639","type":"journal-article","created":{"date-parts":[[2023,7,6]],"date-time":"2023-07-06T13:30:05Z","timestamp":1688650205000},"page":"2148-2160","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["<scp>I\u0138B<\/scp> Protein <scp>BCL3<\/scp> as a Controller of Osteogenesis and Bone Health"],"prefix":"10.1002","volume":"75","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1408-3260","authenticated-orcid":false,"given":"Hussain","family":"Jaffery","sequence":"first","affiliation":[{"name":"School of Infection &amp; 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