Kbus/Idr, a mutant mouse strain with skeletal abnormalities and hypophosphatemia: Identification as an allele of 'Hyp'

Journal of Biomedical Science

Takayuki Takahashi²  Atsushi Kimura²  Katsueki Ogiwara²  Atsushi Yoshiki³  Kazuyuki Mekada³  Atsuko Hanai⁴  Kenji Moriyama¹ 

[1] Department of Medicine & Clinical Science, School of Pharmacy and Pharmaceutical Sciences, Mukogawa Women's University, Nishinomiya 663-8179, Japan;Laboratory of Reproductive and Developmental Biology, Faculty of Science, Hokkaido University, Sapporo 060-0810, Japan;Division of Experimental Animal Research, BioResource Center, RIKEN Tsukuba Institute, Tsukuba 305-0074, Japan;Department of Developmental Biology, Institute for Developmental Research, Aichi Human Service Center, Kasugai 487-0392, Japan

关键词: XLH;    Hyp;    Phex;    Mouse model;    Hypophosphatemia;    Bone defects;   

Others  :  829591
DOI  :  10.1186/1423-0127-18-60

 received in 2011-04-03, accepted in 2011-08-20,  发布年份 2011

【 摘 要 】

Background

The endopeptidase encoded by Phex (phosphate-regulating gene with homologies to endopeptidases linked to the X chromosome) is critical for regulation of bone matrix mineralization and phosphate homeostasis. PHEX has been identified from analyses of human X-linked hypophosphatemic rickets and Hyp mutant mouse models. We here demonstrated a newly established dwarfism-like Kbus/Idr mouse line to be a novel Hyp model.

Methods

Histopathological and X-ray examination with cross experiments were performed to characterize Kbus/Idr. RT-PCR-based and exon-directed PCR screening performed to identify the presence of genetic alteration. Biochemical assays were also performed to evaluate activity of alkaline phosphatase.

Results

Kbus/Idr, characterized by bone mineralization defects, was found to be inherited in an X chromosome-linked dominant manner. RT-PCR experiments showed that a novel mutation spanning exon 16 and 18 causing hypophosphatemic rickets. Alkaline phosphatase activity, as an osteoblast marker, demonstrated raised levels in the bone marrow of Kbus/Idr independent of the age.

Conclusions

Kbus mice should serve as a useful research tool exploring molecular mechanisms underlying aberrant Phex-associated pathophysiological phenomena.

【 授权许可】

   
2011 Moriyama et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

【 参考文献 】

• [1]Moriyama K, Hashimoto R, Hanai A, Yoshizaki N, Yonezawa S, Otani H: Degenerative hairlets on the vestibular sensory cells in mutant bustling (BUS/Idr) mice. Acta Otolaryn 1997, 117:20-24.
• [2]Yonezawa S, Yoshizaki N, Kageyama T, Takahashi T, Sano M, Tokita Y, Masaki1 S, Inaguma Y, Hanai A, Sakurai N, Yoshiki A, Kusakabe M, Moriyama A, Nakayama A: Fates of Cdh23/CDH23 with mutations affecting the cytoplasmic region. Hum Mutat 2006, 27:88-97.
• [3]Kiela PR, Ghishan FK: Recent advances in the renal-skeletal-gut axis that controls phosphate homeostasis. Lab Invest 2009, 89:7-14.
• [4]Bergwitz C, Jüppner H: Regulation of phosphate homeostasis by PTH, vitamin D, and FGF23. Ann Rev Med 2010, 61:91-104.
• [5]ADHR Consortium: Autosomal dominant hypophosphatemic rickets is associated with mutations in FGF-23. Nat Genet 2000, 26:345-348.
• [6]Larsson T, Yu X, Davis SI, Draman MS, Mooney SD, Cullen MJ, White KE: A novel recessive mutation in fibroblast growth factor-23 causes familial tumoral calcinosis. J Clin Endocrinol Metab 2005, 90:2424-2427.
• [7]Larsson T, Davis SI, Garringer HJ, Mooney SD, Draman MS, Cullen MJ, White KE: Fibroblast growth factor-23 mutants causing familial tumoral calcinosis are differentially processed. Endocrinology 2005, 146:3883-3891.
• [8]Yoshiko Y, Wang H, Minamizaki T, Ijuin C, Yamamoto R, Suemune S, Kozai K, Tanne K, Aubin JE, Maeda N: Mineralized tissue cells are a principal source of FGF23. Bone 2007, 40:1565-1573.
• [9]Ubaidus S, Li M, Sultana S, de Freitas PH, Oda K, Maeda T, Takagi R, Amizuka N: FGF23 is mainly synthesized by osteocytes in the regularly distributed osteocytic lacunar canalicular system established after physiological bone remodeling. J Electron Microsc (Tokyo) 2009, 56:381-392.
• [10]Urakawa I, Yamazaki Y, Shimada T, Iijima K, Hasegawa H, Okawa K, Fujita T, Fukumoto S, Yamashita T: Klotho converts canonical FGF receptor into a specific receptor for FGF-23. Nature 2006, 444:770-774.
• [11]Razzaque MS, Lanske B: The emerging role of the fibroblast growth factor-23-klotho axis in renal regulation of phosphate homeostasis. J Endocrinol 2007, 194:1-10.
• [12]The HYP Consortium: A gene (PEX) with homologies to endopeptidases is mutated in patients with X-linked hypophosphatemic rickets. Nat Genet 1995, 11:130-136.
• [13]Strom TM, Francis F, Lorenz B, Böddrich A, Econs MJ, Lehrach H, Meitinger T: Pex gene deletions in Gy and Hyp mice provide mouse models for X-linked hypophosphatemia. Hum Mol Genet 1997, 6:165-171.
• [14]Beck L, Soumounou Y, Martel J, Krishnamurthy G, Gauthier C, Goodyer CG, Tenenhouse HS: Pex/PEX tissue distribution and evidence for a deletion in the 3' region of the Pex gene in X-linked hypophosphatemic mice. J Clin Invest 1997, 99:1200-1209.
• [15]Qiu ZQ, Travers R, Rauch F, Glorieux FH, Scriver CR, Tenenhouse HS: Effect of gene dose and parental origin on bone histomorphometry in X-linked Hyp mice. Bone 2004, 34:134-139.
• [16]Miao D, Bai X, Panda DK, Karaplis AC, Goltzman D, McKee MD: Cartilage abnormalities are associated with abnormal Phex expression and with altered matrix protein and MMP-9 localization in Hyp mice. Bone 2004, 34:638-647.
• [17]Liang G, Katz LD, Insogna KL, Carpenter TO, Macica CM: Survey of the enthesopathy of X-linked hypophosphatemia and its characterization in Hyp mice. Calcif Tissue Int 2009, 85:235-246.
• [18]Fong H, Chu EY, Tompkins KA, Foster BL, Sitara D, Lanske B, Somerman MJ: Aberrant cementum phenotype associated with the hypophosphatemic hyp mouse. J Periodontol 2009, 80:1348-1354.
• [19]Sabbagh Y, Tenenhouse HS, Roche PC, Drezner MK, Salisbury JL, Grande JP, Poeschla EM, Kumar R: Ontogeny of Phex/PHEX protein expression in mouse embryo and subcellular localization in osteoblasts. J Bone Miner Res 2002, 17:311-320.
• [20]Yuan B, Takaiwa M, Clemens TL, Feng JQ, Kumar R, Rowe PS, Xie Y, Drezner MK: Aberrant Phex function in osteoblasts and osteocytes alone underlies murine X-linked hypophosphatemia. J Clin Invest 2008, 118:722-734.
• [21]Guo R, Rowe PS, Liu S, Simpson LG, Xiao ZS, Quarles LD: Inhibition of MEPE cleavage by Phex. Biochem Biophys Res Commun 2002, 297:38-45.
• [22]Rowe PS, Kumagai Y, Gutierrez G, Garrett IR, Blacher R, Rosen D, Cundy J, Navvab S, Chen D, Drezner MK, Quarles LD, Mundy GR: MEPE has the properties of an osteoblastic phosphatonin and minhibin. Bone 2004, 34:303-319.
• [23]Bresler D, Bruder J, Mohnike K, Fraser WD, Rowe PS: Serum EMPE-ASARM-peptides are elevated in X-linked rickets (HYP):Implications for phosphaturia and rickets. J Endocrinol 2004, 183:R1-R9.
• [24]Rowe PS, Garrett IR, Schwarz PM, Carnes DL, Lafer EM, Mundy GR, Gutierrez GE: Surface plasmon resonance (SPR) confirms that MEPE binds to PHEX via the MEPE-ASARM motif:a model for impaired mineralization in X-linked rickets (HYP). Bone 2005, 36:33-46.
• [25]Liu S, Rowe PSN, Vierthaler L, Zhou J, Quarles LD: 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 2007, 192:261-267.
• [26]Addison WN, Nakano Y, Loisel T, Crine P, McKee MD: MEPE-ASARM peptides control extracellular matrix mineralization by binding to hydroxyapatite: an inhibition regulated by PHEX cleavage of ASARM. J Bone Miner Res 2008, 23:1638-1649.
• [27]Martin A, David V, Laurence JS, Schwarz PM, Lafer EM, Hedge AM, Rowe PS: Degradation of MEPE, DMP1, and release of SIBLING ASARM-peptides (minhibins): ASARM-peptide(s) are directly responsible for defective mineralization in HYP. Endocrinology 2008, 149:1757-1772.
• [28]Addison WN, Masica DL, Gray JJ, McKee MD: Phosphorylation-dependent inhibition of mineralization by osteopontin ASARM peptides is regulated by PHEX cleavage. J Bone Miner Res 2010, 25:695-705.
• [29]Boukpessi T, Gaucher C, Léger T, Salmon B, Le Faouder J, Willig C, Rowe PS, Garabédian M, Meilhac O, Chaussain C: Abnormal presence of the matrix extracellular phosphoglycoprotein-derived acidic serine- and aspartate-rich motif peptide in human hypophosphatemic dentin. Am J Pathol 2010, 177:803-812.
• [30]Fisher LW, Fedarko NS: Six genes expressed in bones and teeth encode the current members of the SIBLING family of proteins. Connect Tissue Res 2003, 44(Suppl1):33-40.
• [31]Dobbie H, Unwin RJ, Faria NJ, Shirley DG: Matrix extracellular phosphoglycoprotein causes phosphaturia in rats by inhibiting tubular phosphate reabsorption. Nephrol Dial Transplant 2007, 23:730-733.
• [32]David V, Martin A, Hedge A-N, Rowe PSN: Matrix extracellular phosphoglycoprotein (MEPE) is a new bone renal hormone and vascularization modulator. Endocrinology 2009, 150:4012-4023.
• [33]Meyer RA Jr, Henley CM, Meyer MH, Morgan PL, Mc-Donald AG, Mills C, Price DK: Partial deletion of both the spermine synthase gene and the Pex gene in the X-linkedhypophosphatemic, gyro (Gy) mouse. Genomics 1998, 48:289-295.
• [34]Carpinelli MR, Wicks IP, Sims NA, O'Donnell K, Hanzinikolas K, Burt R, Foote SJ, Bahlo M, Alexander WS, Hilton DJ: An ethyl-nitrosourea-induced point mutation in phex causes exon skipping, x-linked hypophosphatemia, and rickets. Am J Pathol 2002, 161:1925-1933.
• [35]Lorenz-Depiereux B, Guido VE, Johnson KR, Zheng QY, Gagnon LH, Bauschatz JD, Davisson MT, Washburn LL, Donahue LR, Strom TM, Eicher EM: New intragenic deletions in the Phex gene clarify X-linked hypophosphatemia-related abnormalities in mice. Mamm Genome 2004, 15:151-161.
• [36]Xiong X, Qi X, Ge X, Gu P, Zhao J, Zhao Q, Gao X: A novel Phex mutation with defective glycosylation causes hypophosphatemia and rickets in mice. J Biomed Sci 2008, 15:47-59.
• [37]Holm IA, Nelson AE, Robinson BG, Mason RS, Marsh DJ, Cowell CT, Carpenter TO: Mutational analysis and genotype-phenotype correlation of the PHEX gene in X-linked hypophosphatemic rickets. J Clin Endocrinol Metab 2001, 86:3889-3899.
• [38]Ichikawa S, Traxler EA, Estwick SA, Curry LR, Johnson ML, Sorenson AH, Imel EA, Econs MJ: Mutational survey of the PHEX gene in patients with X-linked hypophosphatemic rickets. Bone 2008, 43:663-666.
• [39]Makras P, Hamdy NA, Kant SG, Papapoulos SE: Normal growth and muscle dysfunction in X-linked hypophosphatemic rickets associated with a novel mutation in the PHEX gene. J Clin Endocrinol Metab 2008, 93:1386-1389.
• [40]Gaucher C, Walrant-Debray O, Nguyen T-M, Esterle L, Garabédian M, Jehan F: PHEX analysis in 118 pedigrees reveals new genetic clues in hypophosphatemic rickets. Hum Genet 2009, 125:401-411.
• [41]Ruppe MD, Brosnan PG, Au KS, Tran PX, Dominguez BW, Northrup H: Mutational analysis of PHEX, FGF23 and DMP1 in a cohort of patients with hypophosphatemic rickets. Clin Endocrinol (Oxf) 2011, 74:312-318.
• [42]Fiske CH, SubbaRow Y: The colorimetric determination of phosphorus. J Biol Chem 1925, 66:375-400.
• [43]Megerian CA, Semaan MT, Aftab S, Kisley LB, Zheng QY, Pawlowski KS, Wright CG, Alagramam KN: A mouse model with postnatal endolymphatic hydrops and hearing loss. Hear Res 2008, 237:90-105.
• [44]Wang X, Levic S, Gratton MA, Doyle KJ, Yamoah EN, Pegg AE: Spermine synthase deficiency leads to deafness and a profound sensitivity to alpha-difluoromethylornithine. J Biol Chem 2009, 284:930-937.
• [45]Fishman G, Miller-Hansen D, Jacobsen C, Singhal VK, Alon US: Hearing impairment in familial X-linked hypophosphatemic rickets. Eur J Pediatr 2004, 163:622-623.
• [46]Yamazaki Y, Okazaki R, Shibata M, Hasegawa Y, Satoh K, Tajima T, Takeuchi Y, Fujita T, Nakahara K, Yamashita T, Fukumoto S: Increased circulatory level of biologically active full-length FGF-23 in patients with hypophosphatemic rickets/osteomalacia. J Clin Endocrinol Metab 2002, 87:4957-4960.
• [47]Weber TJ, Liu S, Indridason OS, Quarles LD: Serum FGF23 levels in normal and disordered phosphorus homeostasis. J Bone Miner Res 2003, 18:1227-1234.
• [48]Jonsson KB, Zahradnik R, Larsson T, White KE, Sugimoto T, Imanishi Y, Yamamoto T, Hampson G, Koshiyama H, Ljunggren O, Oba K, Yang IM, Miyauchi A, Econs MJ, Lavigne J, Juppner H: Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia. N Engl J Med 2003, 348:1656-1663.
• [49]Onishi T, Umemura S, Shintani S, Ooshima T: Phex mutation causes overexpression of FGF23 in teeth. Arch Oral Biol 2008, 53:99-104.
• [50]Dimai HP, Linkhart TA, Linkhart SG, Donahue LR, Beamer WG, Rosen CJ, Farley JR, Baylink DJ: Alkaline phosphatase levels and osteoprogenitor cell numbers suggest bone formation may contribute to peak bone density differences between two inbred strains of mice. Bone 1998, 22:211-216.
• [51]Boskey A, Frank A, Fujimoto Y, Spevak L, Verdelis K, Ellis B, Troiano N, Philbrick W, Carpenter T: The PHEX transgene corrects mineralization defects in 9-month-old hypophosphatemic mice. Calcif Tissue Int 2009, 84:126-137.
• [52]Liu S, Guo R, Tu Q, Quarles LD: Overexpression of Phex in osteoblasts fails to rescure the Hyp mouse phenotype. J Biol Chem 2002, 277:3686-3697.
• [53]Bai X, Miao D, Panda D, Grady S, McKee MD, Goltzman D, Karaplis AC: Partial rescue of the Hyp phenotype by osteoblast-targeted PHEX (phosphate-regulating gene with homologies to endopeptidases onn the X chromosome) expression. Mol Endocrinol 2002, 16:2913-2925.
• [54]Erben GR, Mayer D, Weber K, Jonsson K, Juppner H, Lanske B: Overexpression of human PHEX under the human beta-actin promotor does not fully rescue the Hyp mouse phenotype. J Bone Miner Res 2005, 20:; 1149-1160.
• [55]Nakatani T, Ohnishi M, Razzaque S: Inactivation of klotho function induces hyperphosphatemia even in presence of high serum fibroblast growth factor 23 levels in a genetically engineered hypophosphatemic (Hyp) mouse model. FASEB J 2009, 23:3702-3711.
• [56]Brownstein CA, Zhang J, Stillman A, Ellis B, Troiano N, Adams DJ, Gundberg CM, Lifton RP, Carpenter TO: Increased bone volume and correction of HYP mouse hypophosphatemia in the Klotho/HYP mouse. Endocrinology 2010, 151:492-501.