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In this study, we found that mice lacking the bobby sox homolog (<jats:italic>Bbx<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup>) presented increased FGF23 expression and low phosphate levels in the serum and skeletal abnormalities such as a low bone mineral density (BMD) and bone volume (BV), as well as short and weak bones associated with low bone formation. Osteocyte-specific deletion of <jats:italic>Bbx<\/jats:italic> using Dmp-1-Cre resulted in similar skeletal abnormalities, elevated serum FGF23 levels, and reduced serum phosphate levels. In <jats:italic>Bbx<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice, the expression of sodium phosphate cotransporter 2a (<jats:italic>Npt2a<\/jats:italic>) and <jats:italic>Npt2c<\/jats:italic> in the kidney and <jats:italic>Npt2b<\/jats:italic> in the small intestine, which are negatively regulated by FGF23, was downregulated, leading to phosphate excretion\/wasting and malabsorption. An in vitro <jats:italic>Fgf23<\/jats:italic> promoter analysis revealed that 1,25-dihydroxyvitamin D<jats:sub>3<\/jats:sub> (1,25(OH)<jats:sub>2<\/jats:sub>D<jats:sub>3<\/jats:sub>)-induced transactivation of the <jats:italic>Fgf23<\/jats:italic> promoter was significantly inhibited by BBX overexpression, whereas it was increased following <jats:italic>Bbx<\/jats:italic> knockdown. Interestingly, 1,25(OH)<jats:sub>2<\/jats:sub>D<jats:sub>3<\/jats:sub> induced an interaction of the 1,25(OH)<jats:sub>2<\/jats:sub>D<jats:sub>3<\/jats:sub> receptor (VDR) with BBX and downregulated BBX protein levels. Cycloheximide (CHX) only partially downregulated BBX protein levels, indicating that 1,25(OH)<jats:sub>2<\/jats:sub>D<jats:sub>3<\/jats:sub> regulates BBX protein stability. Furthermore, the ubiquitination of BBX followed by proteasomal degradation was required for the increase in <jats:italic>Fgf23<\/jats:italic> expression induced by 1,25(OH)<jats:sub>2<\/jats:sub>D<jats:sub>3<\/jats:sub>. Collectively, our data demonstrate that BBX negatively regulates <jats:italic>Fgf23<\/jats:italic> expression, and consequently, the ubiquitin-dependent proteasomal degradation of BBX is required for FGF23 expression, thereby regulating phosphate homeostasis and bone development in mice.<\/jats:p>","DOI":"10.1038\/s12276-024-01341-9","type":"journal-article","created":{"date-parts":[[2024,11,1]],"date-time":"2024-11-01T03:02:38Z","timestamp":1730430158000},"page":"2436-2448","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["The transcription factor BBX regulates phosphate homeostasis through the modulation of FGF23"],"prefix":"10.1038","volume":"56","author":[{"given":"Su Jeong","family":"Lee","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ju Ang","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hye Jung","family":"Ihn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5057-8842","authenticated-orcid":false,"given":"Je-Yong","family":"Choi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tae-Yub","family":"Kwon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong-In","family":"Shin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eui-Sic","family":"Cho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong Chul","family":"Bae","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rulang","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jung-Eun","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eui Kyun","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,11,1]]},"reference":[{"key":"1341_CR1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1097\/00005792-200001000-00001","volume":"79","author":"R Subramanian","year":"2000","unstructured":"Subramanian, R. & Khardori, R. 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