The transcription factor BBX regulates phosphate homeostasis through the modulation of FGF23
2
조회
0
다운로드
0
인용
0
참고문헌
초록
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.
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.
참고문헌 (55)
- Subramanian, R., "Severe hypophosphatemia. Pathophysiologic implications, clinical presentations, and treatment", Medicine, 79, pp.1~8 (2000)
- Florenzano, P., "Approach to patients with hypophosphataemia", Lancet Diab. Endocrinol, 8, pp.163~174 (2020)
- Fukumoto, S., "Phosphate metabolism and vitamin D", Bonekey Rep, 3, pp.497~ (2014)
- Jüppner, H., "Phosphate and FGF-23", Kidney Int. Suppl, 79, pp.S24~S27 (2011)
- Torres, P. A., "Three feedback loops precisely regulating serum phosphate concentration", Kidney Int, 80, pp.443~445 (2011)
- Bacic, D., "The renal Na+", phosphate cotransporter NaPi-IIa is internalized via the receptor-mediated endocytic route in response to parathyroid hormone, 2006, pp.69, 495~503
- Fraser, D. R., "Regulation of 25-hydroxycholecalciferol-1-hydroxylase activity in kidney by parathyroid hormone", Nat. N. Biol, 241, pp.163~166 (1973)
- Liu, S., "Fibroblast growth factor 23 is a counter-regulatory phosphaturic hormone for vitamin D", J. Am. Soc. Nephrol, 17, pp.1305~1315 (2006)
- Liu, S., "Pathogenic role of Fgf23 in Hyp mice", Am. J. Physiol. Endocrinol. Metab, 291, pp.E38~E49 (2006)
- Masuyama, R., "Vitamin D receptor in chondrocytes promotes osteoclastogenesis and regulates FGF23 production in osteoblasts", J. Clin. Invest, 116, pp.3150~3159 (2006)
- Gattineni, J., "FGF23 decreases renal NaPi-2a and NaPi-2c expression and induces hypophosphatemia in vivo predominantly via FGF receptor 1", Am. J. Physiol. Ren. Physiol, 297, pp.F282~F291 (2009)
- Shimada, T., "Targeted ablation of Fgf23 demonstrates an essential physio logical role of FGF23 in phosphate and vitamin D metabolism", J. Clin. Invest, 113, pp.561~568 (2004)
- Shimada, T., "FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis", J. Bone Min. Res, 19, pp.429~435 (2004)
- Ben-Dov, I. Z., "The parathyroid is a target organ for FGF23 in rats", J. Clin. Invest, 117, pp.4003~4008 (2007)
- Krajisnik, T., "Fibroblast growth factor-23 regulates parathyroid hormone and 1alpha-hydroxylase expression in cultured bovine parathyroid cells", J. Endocrinol, 195, pp.125~131 (2007)
- Takashi, Y., "FGF23 beyond phosphotropic hormone", Trends Endocrinol. Metab, 29, pp.755~767 (2018)
- Shiber, J. R., "Serum phosphate abnormalities in the emergency department", J. Emerg. Med, 23, pp.395~400 (2002)
- Imel, E. A., "Approach to the hypophosphatemic patient", J. Clin. Endocrinol. Metab, 97, pp.696~706 (2012)
- Bitzan, M., "Hypophosphatemic rickets", Pediatr. Clin. North Am, 66, pp.179~207 (2019)
- Jagtap, V. S., "Hypophosphatemic rickets", Indian J. Endocrinol. Metab, 16, pp.177~182 (2012)
- Chen, T., "Characterization of Bbx, a member of a novel subfamily of the HMG-box superfamily together with Cic", Dev. Genes Evol, 224, pp.261~268 (2014)
- Hrckulak, D., "TCF", LEF transcription factors : an update from the internet resources, 2016, pp.8, 70~
- Sanchez-Diaz, A., "HBP2: a new mammalian protein that complements the fission yeast MBF transcription complex", Curr. Genet, 40, pp.110~118 (2001)
- Wang, C. Y., "PiggyBac transposon-mediated mutagenesis in rats reveals a crucial role of Bbx in growth and male fertility", Biol. Reprod, 95, pp.51~ (2016)
- Choi, Y. A., "Bobby Sox homology regulates odontoblast differentiation of human dental pulp stem cells", progenitors, 2014, pp.12, 35~
- Ihn, H. J., "Bobby sox homolog regulates tooth root formation through modulation of dentin sialophosphoprotein", J. Cell Physiol, 236, pp.480~488 (2021)
- Bassett, J. H., "Rapid-throughput skeletal phenotyping of 100 knockout mice identifies 9 new genes that determine bone strength", PLoS Genet, 8, pp.e1002858~ (2012)
- Lee, J. M., "Tgfbi deficiency leads to a reduction in skeletal size and degradation of the bone matrix", Calcif. Tissue Int, 96, pp.56~64 (2015)
- Assefa, F., "The neuropeptide spexin promotes the osteoblast differentiation of MC3T3-E1 cells via the MEK", ERK pathway and bone regeneration in a mouse calvarial defect model, 2022, pp.19, 189~202
- Hong, Y. R., "rhBMP-2-conjugated three-dimensional-printed poly(L-lactide)scaffold is an effective bone substitute", Tissue Eng. Regen. Med, 20, pp.69~81 (2023)
- Shieh, A., "Quantifying the balance between total bone formation and total bone resorption : an index of net bone formation", J. Clin. Endocrinol. Metab, 101, pp.2802~2809 (2016)
- Ott, S. M., "Histomorphometric measurements of bone turnover, mineralization, and volume", Clin. J. Am. Soc. Nephrol, 3, pp.S151~s156 (2008)
- Ammann, P., "Bone strength and its determinants", Osteoporos. Int, 14, pp.S13~S18 (2003)
- Luo, Y., "Bone quality is dependent on the quantity and quality of organic–inorganic phases", J. Med. Biol. Eng, 40, pp.273~281 (2020)
- Fonseca, H., "Bone quality : the determinants of bone strength and fragility", Sports Med, 44, pp.37~53 (2014)
- Follet, H., "The degree of mineralization is a determinant of bone strength : a study on human calcanei", Bone, 34, pp.783~789 (2004)
- Alliston, T., "Bone quality sleuths : uncovering tissue-level mechanisms of bone fragility in human type 2 diabetes", J. Bone Min. Res, 34, pp.1189~1190 (2019)
- Hunt, H. B., "Bone quality assessment techniques: geometric, compositional, and mechanical characterization from macroscale to nanoscale", Clin. Rev. Bone Min. Metab, 14, pp.133~149 (2016)
- Saito, H., "Human fibroblast growth factor-23 mutants suppress Na +-dependent phosphate co-transport activity and 1alpha, 25-dihydroxyvitamin D3 production", J. Biol. Chem, 278, pp.2206~2211 (2003)
- Shimada, T., "FGF-23 transgenic mice demonstrate hypophosphatemic rickets with reduced expression of sodium phosphate cotransporter type IIa", Biochem Biophys. Res. Commun, 314, pp.409~414 (2004)
- Liu, S., "Phosphorylated acidic serine-aspartate-rich MEPE-associated motif peptide from matrix extracellular phosphoglycoprotein inhibits phosphate regulating gene with homologies to endopeptidases on the X-chromosome enzyme activity", J. Endocrinol, 192, pp.261~267 (2007)
- Martin, A., "Regulation and function of the FGF23", klotho endocrine pathways, 2012, pp.92, 131~155
- Sharma, S., "StatPearls" (2021), StatPearls Publishing
- Tiosano, D., "Hypophosphatemia : the common denominator of all rickets", J. Bone Min. Metab, 27, pp.392~401 (2009)
- Feng, J. Q., "Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism", Nat. Genet, 38, pp.1310~1315 (2006)
- Guo, R., "Inhibition of MEPE cleavage by Phex", Biochem Biophys. Res. Commun, 297, pp.38~45 (2002)
- Quarles, L. D., "FGF23, PHEX, and MEPE regulation of phosphate homeostasis and skeletal mineralization", Am. J. Physiol. Endocrinol. Metab, 285, pp.E1~E9 (2003)
- Lorenz-Depiereux, B., "Loss-of function ENPP1 mutations cause both generalized arterial calcification of infancy and autosomal-recessive hypophosphatemic rickets", Am. J. Hum. Genet, 86, pp.267~272 (2010)
- Su, N., "Role of FGF", FGFR signaling in skeletal development and homeostasis : learning from mouse models, 2014, pp.2, 14003~
- Agoro, R., "Osteocytic FGF23 and its kidney function", Front Endocrinol, 11, pp.592~ (2020)
- Liu, S., "Pathogenic role of Fgf23 in Dmp1-null mice", Am. J. Physiol. Endocrinol. Metab, 295, pp.E254~E261 (2008)
- Ichikawa, S., "A mutation in the Dmp1 gene alters phosphate responsiveness in mice", Endocrinology, 158, pp.470~476 (2017)
- Mackenzie, N. C., "Altered bone development and an increase in FGF-23expression in Enpp1(-", -)mice, 2012, pp.7, e32177~
- Ewendt, F., "Peroxisome proliferator-activated receptor α(PPARα)-dependent regulation of fibroblast growth factor 23(FGF23)", Pflug. Arch, 472, pp.503~511 (2020)
- Salehi-Tabar, R., "The tumor suppressor FBW7 and the vitamin D receptor are mutual cofactors in protein turnover and transcriptional regulation", Mol. Cancer Res, 17, pp.709~719 (2019)