한빛사논문
- 조회236
Su Jeong Lee 1, Ju Ang Kim 1, Hye Jung Ihn 2, Je-Yong Choi 3, Tae-Yub Kwon 4, Hong-In Shin 1, Eui-Sic Cho 5, Yong Chul Bae 6, Rulang Jiang 7, Jung-Eun Kim 2,8 and Eui Kyun Park 1,*
1Department of Oral Pathology and Regenerative Medicine, School of Dentistry, Institute for Hard Tissue and Bio‑tooth Regeneration (IHBR), Kyungpook National University, Daegu, Republic of Korea.
2Cell and Matrix Research Institute, Kyungpook National University, Daegu, Republic of Korea.
3Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
4Department of Dental Biomaterials, School of Dentistry, Kyungpook National University, Daegu, Republic of Korea.
5Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Biosciences, School of Dentistry, Jeonbuk National University, Jeonju, Republic of Korea.
6Department of Oral Anatomy and Neurobiology, School of Dentistry, Kyungpook National University, Daegu, Republic of Korea.
7Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Ohio, TX, USA.
8Department of Molecular Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
*Corresponding author: correspondence to Eui Kyun Park
Abstract
Fibroblast growth factor 23 (FGF23) plays an important role in phosphate homeostasis, and increased FGF23 levels result in hypophosphatemia; however, the molecular mechanism underlying increased FGF23 expression has not been fully elucidated. In this study, we found that mice lacking the bobby sox homolog (Bbx−/−) 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 Bbx using Dmp-1-Cre resulted in similar skeletal abnormalities, elevated serum FGF23 levels, and reduced serum phosphate levels. In Bbx−/− mice, the expression of sodium phosphate cotransporter 2a (Npt2a) and Npt2c in the kidney and Npt2b in the small intestine, which are negatively regulated by FGF23, was downregulated, leading to phosphate excretion/wasting and malabsorption. An in vitro Fgf23 promoter analysis revealed that 1,25-dihydroxyvitamin D3 (1,25(OH)2D3)-induced transactivation of the Fgf23 promoter was significantly inhibited by BBX overexpression, whereas it was increased following Bbx knockdown. Interestingly, 1,25(OH)2D3 induced an interaction of the 1,25(OH)2D3 receptor (VDR) with BBX and downregulated BBX protein levels. Cycloheximide (CHX) only partially downregulated BBX protein levels, indicating that 1,25(OH)2D3 regulates BBX protein stability. Furthermore, the ubiquitination of BBX followed by proteasomal degradation was required for the increase in Fgf23 expression induced by 1,25(OH)2D3. Collectively, our data demonstrate that BBX negatively regulates Fgf23 expression, and consequently, the ubiquitin-dependent proteasomal degradation of BBX is required for FGF23 expression, thereby regulating phosphate homeostasis and bone development in mice.
논문정보
- Research article
- 2024년 11월 (BRIC 등록일 2024-11-05)
- 국내 연구진
- 의약학 > 의약학 기타
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