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Takeyoshi Yamashita - One of the best experts on this subject based on the ideXlab platform.
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therapeutic effects of anti fgf23 antibodies in hypophosphatemic rickets osteomalacia
Journal of Bone and Mineral Research, 2009Co-Authors: Yukiko Aono, Hisashi Hasegawa, Itaru Urakawa, Yuji Yamazaki, Takeyoshi Yamashita, Toshiro Fujita, Junichi Yasutake, Takehisa Kawata, Michihito Wada, Seiji FukumotoAbstract:X-linked Hypophosphatemia (XLH), characterized by renal phosphate wasting, is the most common cause of vitamin D-resistant rickets. It has been postulated that some phosphaturic factor plays a causative role in XLH and its murine homolog, the Hyp mouse. Fibroblast growth factor 23 (FGF23) is a physiological phosphaturic factor; its circulatory level is known to be high in most patients with XLH and Hyp mice, suggesting its pathophysiological role in this disease. To test this hypothesis, we treated Hyp mice with anti-FGF23 antibodies to inhibit endogenous FGF23 action. A single injection of the antibodies corrected the Hypophosphatemia and inappropriately normal serum 1,25-dihydroxyvitamin D. These effects were accompanied by increased expressions of type IIa sodium-phosphate cotransporter and 25-hydroxyvitamin-D-1α-hydroxylase and a suppressed expression of 24-hydroxylase in the kidney. Repeated injections during the growth period ameliorated the rachitic bone phenotypes typically observed in Hyp mice, such as impaired longitudinal elongation, defective mineralization, and abnormal cartilage development. Thus, these results indicate that excess actions of FGF23 underlie hypophosphatemic rickets in Hyp mice and suggest a novel therapeutic potential of the FGF23 antibodies for XLH.
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venous sampling for fibroblast growth factor 23 confirms preoperative diagnosis of tumor induced osteomalacia
The Journal of Clinical Endocrinology and Metabolism, 2004Co-Authors: Yasuhiro Takeuchi, Yuji Yamazaki, Takeyoshi Yamashita, Hisanori Suzuki, Sayoko Ogura, Rie Imai, Yoshinari Miyamoto, Hiroshi Okazaki, Kozo Nakamura, Kazuhiko NakaharaAbstract:Tumor-induced osteomalacia (TIO) is a paraneoplastic disorder characterized by Hypophosphatemia, phosphaturia, inappropriately low serum levels of 1,25-dihydroxyvitamin D for Hypophosphatemia, and skeletal undermineralization. Patients with TIO suffer from severe muscle weakness and pain. Because surgical removal of the responsible tumors is the only satisfactory treatment for TIO, identification of the tumors is clinically essential. However, because they are predominantly slow-growing neoplasms of benign mesenchymal origin, localization of the responsible tumors is often very difficult. Moreover, even if a tumor is found in a patient with hypophosphatemic osteomalacia, we have had no way to know that the tumor is actually causing the disease. Fibroblast growth factor-23 (FGF-23) was recently identified as a causative factor for TIO and was shown to induce renal phosphate wasting. We have recently shown that the circulatory FGF-23 level was high in a patient with TIO and rapidly decreased after removal of the responsible tumor. For the first time, we describe a patient with adult-onset hypophosphatemic osteomalacia in whom a clinical diagnosis of TIO was confirmed before surgical removal of the tumor by localizing the responsible tumor using venous sampling for FGF-23 together with magnetic resonance imaging. This combinatorial procedure would be clinically useful for sporadic cases of hypophosphatemic rickets/osteomalacia.
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venous sampling for fibroblast growth factor 23 confirms preoperative diagnosis of tumor induced osteomalacia
The Journal of Clinical Endocrinology and Metabolism, 2004Co-Authors: Yasuhiro Takeuchi, Yuji Yamazaki, Takeyoshi Yamashita, Hisanori Suzuki, Sayoko Ogura, Rie Imai, Yoshinari Miyamoto, Hiroshi Okazaki, Kozo Nakamura, Kazuhiko NakaharaAbstract:Tumor-induced osteomalacia (TIO) is a paraneoplastic disorder characterized by Hypophosphatemia, phosphaturia, inappropriately low serum levels of 1,25-dihydroxyvitamin D for Hypophosphatemia, and skeletal undermineralization. Patients with TIO suffer from severe muscle weakness and pain. Because surgical removal of the responsible tumors is the only satisfactory treatment for TIO, identification of the tumors is clinically essential. However, because they are predominantly slow-growing neoplasms of benign mesenchymal origin, localization of the responsible tumors is often very difficult. Moreover, even if a tumor is found in a patient with hypophosphatemic osteomalacia, we have had no way to know that the tumor is actually causing the disease. Fibroblast growth factor-23 (FGF-23) was recently identified as a causative factor for TIO and was shown to induce renal phosphate wasting. We have recently shown that the circulatory FGF-23 level was high in a patient with TIO and rapidly decreased after removal of the responsible tumor. For the first time, we describe a patient with adult-onset hypophosphatemic osteomalacia in whom a clinical diagnosis of TIO was confirmed before surgical removal of the tumor by localizing the responsible tumor using venous sampling for FGF-23 together with magnetic resonance imaging. This combinatorial procedure would be clinically useful for sporadic cases of hypophosphatemic rickets/osteomalacia. (J Clin Endocrinol Metab 89: 3979 –3982, 2004)
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fgf 23 transgenic mice demonstrate hypophosphatemic rickets with reduced expression of sodium phosphate cotransporter type iia
Biochemical and Biophysical Research Communications, 2004Co-Authors: Takashi Shimada, Hisashi Hasegawa, Rieko Hino, Takashi Yoneya, Itaru Urakawa, Yuji Yamazaki, Seiji Fukumoto, Toshiro Fujita, Yasuhiro Takeuchi, Takeyoshi YamashitaAbstract:Fibroblast growth factor (FGF)-23 was identified as a causative factor of tumor-induced osteomalacia and also as a responsible gene for autosomal dominant hypophosphatemic rickets. To clarify the pathophysiological roles of FGF-23 in these diseases, we generated its transgenic mice. The transgenic mice expressing human FGF-23 reproduced the common clinical features of these diseases such as Hypophosphatemia probably due to increased renal phosphate wasting, inappropriately low serum 1,25-dihydroxyvitamin D level, and rachitic bone. The renal phosphate wasting in the transgenic mice was accompanied by the reduced expression of sodium phosphate cotransporter type IIa in renal proximal tubules. These results reinforce the notion that the excessive action of FGF-23 plays a causative role in the development of several hypophosphatemic rickets/osteomalacia.
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fgf 23 is a potent regulator of vitamin d metabolism and phosphate homeostasis
Journal of Bone and Mineral Research, 2003Co-Authors: Takashi Shimada, Hisashi Hasegawa, Rieko Hino, Yuji Yamazaki, Seiji Fukumoto, Toshiro Fujita, Yasuhiro Takeuchi, Kazuhiko Nakahara, Takanori Muto, Takeyoshi YamashitaAbstract:We analyzed the effects of an FGF-23 injection in vivo. FGF-23 caused a reduction in serum 1,25-dihydroxyvitamin D by altering the expressions of key enzymes for the vitamin D metabolism followed by Hypophosphatemia. This study indicates that FGF-23 is a potent regulator of the vitamin D and phosphate metabolism. Introduction: The pathophysiological contribution of FGF-23 in hypophosphatemic diseases was supported by animal studies in which the long-term administration of recombinant fibroblast growth factor-23 reproduced hypophosphatemic rickets with a low serum 1,25-dihydroxyvitamin D [1,25(OH)2D] level. However, there is no clear understanding of how FGF-23 causes these changes. Materials and Methods: To elucidate the molecular mechanisms of the FGF-23 function, we investigated the short-term effects of a single administration of recombinant FGF-23 in normal and parathyroidectmized animals. Results: An injection of recombinant FGF-23 caused a reduction in serum phosphate and 1,25(OH)2D levels. A decrease in serum phosphate was first observed 9 h after the injection and was accompanied with a reduction in renal mRNA and protein levels for the type IIa sodium-phosphate cotransporter (NaPi-2a). There was no increase in the parathyroid hormone (PTH) level throughout the experiment, and Hypophosphatemia was reproduced by FGF-23 in parathyroidectomized rats. Before this hypophosphatemic effect, the serum 1,25(OH)2D level had already descended at 3 h and reached the nadir 9 h after the administration. FGF-23 reduced renal mRNA for 25-hydroxyvitamin D-1α-hydroxylase and increased that for 25-hydroxyvitamin D-24-hydroxylase starting at 1 h. In addition, an injection of calcitriol into normal mice increased the serum FGF-23 level within 4 h. Conclusions: FGF-23 regulates NaPi-2a independently of PTH and the serum 1,25(OH)2D level by controlling renal expressions of key enzymes of the vitamin D metabolism. In conclusion, FGF-23 is a potent regulator of phosphate and vitamin D homeostasis.
Toshiro Fujita - One of the best experts on this subject based on the ideXlab platform.
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therapeutic effects of anti fgf23 antibodies in hypophosphatemic rickets osteomalacia
Journal of Bone and Mineral Research, 2009Co-Authors: Yukiko Aono, Hisashi Hasegawa, Itaru Urakawa, Yuji Yamazaki, Takeyoshi Yamashita, Toshiro Fujita, Junichi Yasutake, Takehisa Kawata, Michihito Wada, Seiji FukumotoAbstract:X-linked Hypophosphatemia (XLH), characterized by renal phosphate wasting, is the most common cause of vitamin D-resistant rickets. It has been postulated that some phosphaturic factor plays a causative role in XLH and its murine homolog, the Hyp mouse. Fibroblast growth factor 23 (FGF23) is a physiological phosphaturic factor; its circulatory level is known to be high in most patients with XLH and Hyp mice, suggesting its pathophysiological role in this disease. To test this hypothesis, we treated Hyp mice with anti-FGF23 antibodies to inhibit endogenous FGF23 action. A single injection of the antibodies corrected the Hypophosphatemia and inappropriately normal serum 1,25-dihydroxyvitamin D. These effects were accompanied by increased expressions of type IIa sodium-phosphate cotransporter and 25-hydroxyvitamin-D-1α-hydroxylase and a suppressed expression of 24-hydroxylase in the kidney. Repeated injections during the growth period ameliorated the rachitic bone phenotypes typically observed in Hyp mice, such as impaired longitudinal elongation, defective mineralization, and abnormal cartilage development. Thus, these results indicate that excess actions of FGF23 underlie hypophosphatemic rickets in Hyp mice and suggest a novel therapeutic potential of the FGF23 antibodies for XLH.
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familial hypophosphatemic rickets caused by a large deletion in phex gene
European Journal of Endocrinology, 2009Co-Authors: T. Saito, Toshiyuki Yasuda, Yutaka Nishii, Seiji Fukumoto, Takashi Igarashi, Hisanori Suzuki, Toshiro FujitaAbstract:Context: X-linked hypophosphatemic rickets/osteomalacia (XLH), autosomal dominant and recessive hypophosphatemic rickets/osteomalacia (ADHR and ARHR) share common clinical features including high fibroblast growth factor 23 (FGF23) levels. These diseases are caused by mutations in phosphate regulating endopeptidase homolog, X-linked (PHEX),FGF23, and dentin matrix acidic phosphoprotein 1 (DMP1) gene respectively. It remains unclear whether these diseases can be clinically discriminated. Objective: To clarify the underlying mechanism of patients with hypophosphatemic rickets whose parents showed no physical findings suggesting rickets. Design and patients: The proband is a 39-year-old woman. She and her 37-year-old brother show the same clinical features such as bowing of legs together with Hypophosphatemia (sister: P 1.8 mg/dl, brother: P 1.6 mg/dl) and high FGF23 levels (sister: 542 pg/ml, brother: 96 pg/ml). Physical findings of their parents are normal and ARHR was suspected. Results: Sequencing of all coding exons and exon‐intron junctions ofDMP1 andFGF23 genes showed no mutation. Subsequent analysis revealed that there is a deletion of 52 143 bp including exons 1‐3 in PHEX gene in the brother. His sister was found to be a heterozygote for the same deletion indicating that they are suffering from XLH. The same deletion was detected in the mother. However, the amount of the wild-type allele was more and that of the mutant one was less in genomic DNA from the mother compared with those from the sister. Single nucleotide polymorphism (SNP) analysis indicated that the mother has three kinds of PHEX alleles suggesting a somatic mosaicism. Conclusion: Careful genetic analysis is mandatory for correct differential diagnosis of hypophosphatemic rickets with high FGF23 levels.
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familial hypophosphatemic rickets caused by a large deletion in phex gene
European Journal of Endocrinology, 2009Co-Authors: T. Saito, Toshiyuki Yasuda, Yutaka Nishii, Seiji Fukumoto, Takashi Igarashi, Hisanori Suzuki, Toshiro FujitaAbstract:Context: X-linked hypophosphatemic rickets/osteomalacia (XLH), autosomal dominant and recessive hypophosphatemic rickets/osteomalacia (ADHR and ARHR) share common clinical features including high fibroblast growth factor 23 (FGF23) levels. These diseases are caused by mutations in phosphate regulating endopeptidase homolog, X-linked (PHEX),FGF23, and dentin matrix acidic phosphoprotein 1 (DMP1) gene respectively. It remains unclear whether these diseases can be clinically discriminated. Objective: To clarify the underlying mechanism of patients with hypophosphatemic rickets whose parents showed no physical findings suggesting rickets. Design and patients: The proband is a 39-year-old woman. She and her 37-year-old brother show the same clinical features such as bowing of legs together with Hypophosphatemia (sister: P 1.8 mg/dl, brother: P 1.6 mg/dl) and high FGF23 levels (sister: 542 pg/ml, brother: 96 pg/ml). Physical findings of their parents are normal and ARHR was suspected. Results: Sequencing of all coding exons and exon‐intron junctions ofDMP1 andFGF23 genes showed no mutation. Subsequent analysis revealed that there is a deletion of 52 143 bp including exons 1‐3 in PHEX gene in the brother. His sister was found to be a heterozygote for the same deletion indicating that they are suffering from XLH. The same deletion was detected in the mother. However, the amount of the wild-type allele was more and that of the mutant one was less in genomic DNA from the mother compared with those from the sister. Single nucleotide polymorphism (SNP) analysis indicated that the mother has three kinds of PHEX alleles suggesting a somatic mosaicism. Conclusion: Careful genetic analysis is mandatory for correct differential diagnosis of hypophosphatemic rickets with high FGF23 levels.
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Hypophosphatemia induced by intravenous administration of saccharated ferric oxide another form of fgf23 related Hypophosphatemia
Bone, 2009Co-Authors: Yuichiro Shimizu, Seiji Fukumoto, Toshitsugu Sugimoto, Hisanori Suzuki, Yuko Tada, Mika Yamauchi, Takaaki Okamoto, Toshiro FujitaAbstract:Abstract Fibroblast growth factor 23 (FGF23) is a humoral factor that is produced by osteocytes and regulates phosphate and vitamin D metabolism. Several hypophosphatemic diseases including X-linked, autosomal dominant and autosomal recessive hypophosphatemic rickets/osteomalacia and tumor-induced rickets/osteomalacia are caused by excess actions of FGF23. These diseases are characterized by Hypophosphatemia associated with impaired proximal tubular phosphate reabsorption and inappropriately low serum 1,25-dihydroxyvitamin D [1,25(OH) 2 D] levels for Hypophosphatemia. Saccharated ferric oxide is widely used in Japan for iron-deficiency anemia. While it has been shown that saccharated ferric oxide induces hypophosphatemic osteomalacia, the mechanism of this Hypophosphatemia remains to be clarified. We here describe three hypophosphatemic patients caused by intravenous administration of saccharated ferric oxide. Hypophosphatemia in these patients were associated with impaired renal tubular phosphate reabsorption, rather low serum 1,25(OH) 2 D and high FGF23 levels. All these biochemical features improved by the cessation of saccharated ferric oxide. These results indicate that Hypophosphatemia caused by saccharated ferric oxide is another form of FGF23-related Hypophosphatemia.
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fgf 23 transgenic mice demonstrate hypophosphatemic rickets with reduced expression of sodium phosphate cotransporter type iia
Biochemical and Biophysical Research Communications, 2004Co-Authors: Takashi Shimada, Hisashi Hasegawa, Rieko Hino, Takashi Yoneya, Itaru Urakawa, Yuji Yamazaki, Seiji Fukumoto, Toshiro Fujita, Yasuhiro Takeuchi, Takeyoshi YamashitaAbstract:Fibroblast growth factor (FGF)-23 was identified as a causative factor of tumor-induced osteomalacia and also as a responsible gene for autosomal dominant hypophosphatemic rickets. To clarify the pathophysiological roles of FGF-23 in these diseases, we generated its transgenic mice. The transgenic mice expressing human FGF-23 reproduced the common clinical features of these diseases such as Hypophosphatemia probably due to increased renal phosphate wasting, inappropriately low serum 1,25-dihydroxyvitamin D level, and rachitic bone. The renal phosphate wasting in the transgenic mice was accompanied by the reduced expression of sodium phosphate cotransporter type IIa in renal proximal tubules. These results reinforce the notion that the excessive action of FGF-23 plays a causative role in the development of several hypophosphatemic rickets/osteomalacia.
Seiji Fukumoto - One of the best experts on this subject based on the ideXlab platform.
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X-Linked Hypophosphatemia and FGF23-Related Hypophosphatemic Diseases: Prospect for New Treatment.
Endocrine reviews, 2018Co-Authors: Yuka Kinoshita, Seiji FukumotoAbstract:Phosphate plays essential roles in many biological processes, and the serum phosphate level is tightly controlled. Chronic Hypophosphatemia causes impaired mineralization of the bone matrix and results in rickets and osteomalacia. Fibroblast growth factor 23 (FGF23) is a bone-derived hormone that regulates phosphate metabolism. FGF23 excess induces Hypophosphatemia via impaired phosphate reabsorption in the renal proximal tubules and decreased phosphate absorption in the intestines. There are several types of genetic and acquired FGF23-related hypophosphatemic diseases. Among these diseases, X-linked Hypophosphatemia (XLH), which is caused by inactivating mutations in the phosphate-regulating endopeptidase homolog, X-linked (PHEX) gene, is the most prevalent form of genetic FGF23-related hypophosphatemic rickets. Another clinically relevant form of FGF23-related hypophosphatemic disease is tumor-induced osteomalacia (TIO), a paraneoplastic syndrome associated with FGF23-producing tumors. A combination of active vitamin D and phosphate salts is the current medical therapy used to treat patients with XLH and inoperative TIO. However, this therapy has certain efficacy- and safety-associated limitations. Several measures to inhibit FGF23 activity have been considered as possible new treatments for FGF23-related hypophosphatemic diseases. In particular, a humanized monoclonal antibody for FGF23 (burosumab) is a promising treatment in patients with XLH and TIO. This review will focus on the phosphate metabolism and the pathogenesis and treatment of FGF23-related hypophosphatemic diseases.
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hypophosphatemic osteomalacia and bone sclerosis caused by a novel homozygous mutation of the fam20c gene in an elderly man with a mild variant of raine syndrome
Bone, 2014Co-Authors: Shinji Takeyari, Seiji Fukumoto, Takehisa Yamamoto, Yuka Kinoshita, Toshimi Michigami, Francis H Glorieux, Kosei Hasegawa, Taichi Kitaoka, Takuo Kubota, Yasuo ImanishiAbstract:Abstract Background Hypophosphatemia and increased serum fibroblast growth factor 23 (FGF23) levels have been reported in young brothers with compound heterozygous mutations for the FAM20C gene; however, rickets was not observed in these cases. We report an adult case of Raine syndrome accompanying hypophosphatemic osteomalacia with a homozygous FAM20C mutation (R408W) associated with increased periosteal bone formation in the long bones and an increase in bone mineral density in the femoral neck. Case The patient, a 61-year-old man, was born from a cousin-to-cousin marriage. A short stature and severe dental demineralization were reported at an elementary school age. Hypophosphatemia was noted inadvertently at 27 years old, at which time he started to take an active vitamin D metabolite (alphacalcidol) and phosphate. He also manifested ossification of the posterior longitudinal ligament. On bone biopsy performed at the age of 41 years, we found severe osteomalacia surrounding osteocytes, which appeared to be an advanced form of periosteocytic hypomineralized lesions compared to those reported in patients with X-linked hypophosphatemic rickets. Laboratory data at 61 years of age revealed markedly increased serum intact-FGF23 levels, which were likely to be the cause of Hypophosphatemia and the decreased level of 1,25(OH) 2 D. We recently identified a homozygous FAM20C mutation, which was R408W, in this patient. When expressed in HEK293 cells, the R408W mutant protein exhibited impaired kinase activity and secretion. Discussion Our findings suggest that certain homozygous FAM20C mutations can cause FGF23-related hypophosphatemic osteomalacia and indicate the multiple roles of FAM20C in bone.
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tumor induced osteomalacia associated with a maxillofacial tumor producing fibroblast growth factor 23 report of a case and review of the literature
Oral Surgery Oral Medicine Oral Pathology Oral Radiology and Endodontology, 2010Co-Authors: Yoshiyuki Mori, Seiji Fukumoto, Yuichiro Shimizu, Toru Ogasawara, Toru Motoi, Daichi Chikazu, Kazumi Tamura, Tsuyoshi TakatoAbstract:Tumor-induced osteomalacia (TIO) is a rare acquired paraneoplastic disease characterized by renal phosphate wasting and Hypophosphatemia. Recently, it was reported that tumors associated with TIO produce fibroblast growth factor (FGF) 23, identified as the last member of the FGF family and of which excessive action causes several hypophosphatemic diseases whereas deficient FGF23 activity results in hyperphosphatemic tumoral calcinosis. In this case, although it was difficult to locate the associated tumor, an abnormal mass in the left maxilla was detected by imaging. The tumor was removed by partial resection of the left maxillary alveolar region. Thereafter, serum level of FGF23 rapidly decreased, Hypophosphatemia improved, and the clinical symptoms greatly improved. Histopathologic diagnosis of the tumor was phosphaturic mesenchymal tumor, mixed connective tissue variant. Immunohistochemical findings confirmed that the removed tumor produced FGF23. These results indicate that development of osteomalacia in this patient was related to the maxillary tumor, which overexpressed FGF23.
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therapeutic effects of anti fgf23 antibodies in hypophosphatemic rickets osteomalacia
Journal of Bone and Mineral Research, 2009Co-Authors: Yukiko Aono, Hisashi Hasegawa, Itaru Urakawa, Yuji Yamazaki, Takeyoshi Yamashita, Toshiro Fujita, Junichi Yasutake, Takehisa Kawata, Michihito Wada, Seiji FukumotoAbstract:X-linked Hypophosphatemia (XLH), characterized by renal phosphate wasting, is the most common cause of vitamin D-resistant rickets. It has been postulated that some phosphaturic factor plays a causative role in XLH and its murine homolog, the Hyp mouse. Fibroblast growth factor 23 (FGF23) is a physiological phosphaturic factor; its circulatory level is known to be high in most patients with XLH and Hyp mice, suggesting its pathophysiological role in this disease. To test this hypothesis, we treated Hyp mice with anti-FGF23 antibodies to inhibit endogenous FGF23 action. A single injection of the antibodies corrected the Hypophosphatemia and inappropriately normal serum 1,25-dihydroxyvitamin D. These effects were accompanied by increased expressions of type IIa sodium-phosphate cotransporter and 25-hydroxyvitamin-D-1α-hydroxylase and a suppressed expression of 24-hydroxylase in the kidney. Repeated injections during the growth period ameliorated the rachitic bone phenotypes typically observed in Hyp mice, such as impaired longitudinal elongation, defective mineralization, and abnormal cartilage development. Thus, these results indicate that excess actions of FGF23 underlie hypophosphatemic rickets in Hyp mice and suggest a novel therapeutic potential of the FGF23 antibodies for XLH.
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familial hypophosphatemic rickets caused by a large deletion in phex gene
European Journal of Endocrinology, 2009Co-Authors: T. Saito, Toshiyuki Yasuda, Yutaka Nishii, Seiji Fukumoto, Takashi Igarashi, Hisanori Suzuki, Toshiro FujitaAbstract:Context: X-linked hypophosphatemic rickets/osteomalacia (XLH), autosomal dominant and recessive hypophosphatemic rickets/osteomalacia (ADHR and ARHR) share common clinical features including high fibroblast growth factor 23 (FGF23) levels. These diseases are caused by mutations in phosphate regulating endopeptidase homolog, X-linked (PHEX),FGF23, and dentin matrix acidic phosphoprotein 1 (DMP1) gene respectively. It remains unclear whether these diseases can be clinically discriminated. Objective: To clarify the underlying mechanism of patients with hypophosphatemic rickets whose parents showed no physical findings suggesting rickets. Design and patients: The proband is a 39-year-old woman. She and her 37-year-old brother show the same clinical features such as bowing of legs together with Hypophosphatemia (sister: P 1.8 mg/dl, brother: P 1.6 mg/dl) and high FGF23 levels (sister: 542 pg/ml, brother: 96 pg/ml). Physical findings of their parents are normal and ARHR was suspected. Results: Sequencing of all coding exons and exon‐intron junctions ofDMP1 andFGF23 genes showed no mutation. Subsequent analysis revealed that there is a deletion of 52 143 bp including exons 1‐3 in PHEX gene in the brother. His sister was found to be a heterozygote for the same deletion indicating that they are suffering from XLH. The same deletion was detected in the mother. However, the amount of the wild-type allele was more and that of the mutant one was less in genomic DNA from the mother compared with those from the sister. Single nucleotide polymorphism (SNP) analysis indicated that the mother has three kinds of PHEX alleles suggesting a somatic mosaicism. Conclusion: Careful genetic analysis is mandatory for correct differential diagnosis of hypophosphatemic rickets with high FGF23 levels.
Yuji Yamazaki - One of the best experts on this subject based on the ideXlab platform.
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therapeutic effects of anti fgf23 antibodies in hypophosphatemic rickets osteomalacia
Journal of Bone and Mineral Research, 2009Co-Authors: Yukiko Aono, Hisashi Hasegawa, Itaru Urakawa, Yuji Yamazaki, Takeyoshi Yamashita, Toshiro Fujita, Junichi Yasutake, Takehisa Kawata, Michihito Wada, Seiji FukumotoAbstract:X-linked Hypophosphatemia (XLH), characterized by renal phosphate wasting, is the most common cause of vitamin D-resistant rickets. It has been postulated that some phosphaturic factor plays a causative role in XLH and its murine homolog, the Hyp mouse. Fibroblast growth factor 23 (FGF23) is a physiological phosphaturic factor; its circulatory level is known to be high in most patients with XLH and Hyp mice, suggesting its pathophysiological role in this disease. To test this hypothesis, we treated Hyp mice with anti-FGF23 antibodies to inhibit endogenous FGF23 action. A single injection of the antibodies corrected the Hypophosphatemia and inappropriately normal serum 1,25-dihydroxyvitamin D. These effects were accompanied by increased expressions of type IIa sodium-phosphate cotransporter and 25-hydroxyvitamin-D-1α-hydroxylase and a suppressed expression of 24-hydroxylase in the kidney. Repeated injections during the growth period ameliorated the rachitic bone phenotypes typically observed in Hyp mice, such as impaired longitudinal elongation, defective mineralization, and abnormal cartilage development. Thus, these results indicate that excess actions of FGF23 underlie hypophosphatemic rickets in Hyp mice and suggest a novel therapeutic potential of the FGF23 antibodies for XLH.
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venous sampling for fibroblast growth factor 23 confirms preoperative diagnosis of tumor induced osteomalacia
The Journal of Clinical Endocrinology and Metabolism, 2004Co-Authors: Yasuhiro Takeuchi, Yuji Yamazaki, Takeyoshi Yamashita, Hisanori Suzuki, Sayoko Ogura, Rie Imai, Yoshinari Miyamoto, Hiroshi Okazaki, Kozo Nakamura, Kazuhiko NakaharaAbstract:Tumor-induced osteomalacia (TIO) is a paraneoplastic disorder characterized by Hypophosphatemia, phosphaturia, inappropriately low serum levels of 1,25-dihydroxyvitamin D for Hypophosphatemia, and skeletal undermineralization. Patients with TIO suffer from severe muscle weakness and pain. Because surgical removal of the responsible tumors is the only satisfactory treatment for TIO, identification of the tumors is clinically essential. However, because they are predominantly slow-growing neoplasms of benign mesenchymal origin, localization of the responsible tumors is often very difficult. Moreover, even if a tumor is found in a patient with hypophosphatemic osteomalacia, we have had no way to know that the tumor is actually causing the disease. Fibroblast growth factor-23 (FGF-23) was recently identified as a causative factor for TIO and was shown to induce renal phosphate wasting. We have recently shown that the circulatory FGF-23 level was high in a patient with TIO and rapidly decreased after removal of the responsible tumor. For the first time, we describe a patient with adult-onset hypophosphatemic osteomalacia in whom a clinical diagnosis of TIO was confirmed before surgical removal of the tumor by localizing the responsible tumor using venous sampling for FGF-23 together with magnetic resonance imaging. This combinatorial procedure would be clinically useful for sporadic cases of hypophosphatemic rickets/osteomalacia.
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venous sampling for fibroblast growth factor 23 confirms preoperative diagnosis of tumor induced osteomalacia
The Journal of Clinical Endocrinology and Metabolism, 2004Co-Authors: Yasuhiro Takeuchi, Yuji Yamazaki, Takeyoshi Yamashita, Hisanori Suzuki, Sayoko Ogura, Rie Imai, Yoshinari Miyamoto, Hiroshi Okazaki, Kozo Nakamura, Kazuhiko NakaharaAbstract:Tumor-induced osteomalacia (TIO) is a paraneoplastic disorder characterized by Hypophosphatemia, phosphaturia, inappropriately low serum levels of 1,25-dihydroxyvitamin D for Hypophosphatemia, and skeletal undermineralization. Patients with TIO suffer from severe muscle weakness and pain. Because surgical removal of the responsible tumors is the only satisfactory treatment for TIO, identification of the tumors is clinically essential. However, because they are predominantly slow-growing neoplasms of benign mesenchymal origin, localization of the responsible tumors is often very difficult. Moreover, even if a tumor is found in a patient with hypophosphatemic osteomalacia, we have had no way to know that the tumor is actually causing the disease. Fibroblast growth factor-23 (FGF-23) was recently identified as a causative factor for TIO and was shown to induce renal phosphate wasting. We have recently shown that the circulatory FGF-23 level was high in a patient with TIO and rapidly decreased after removal of the responsible tumor. For the first time, we describe a patient with adult-onset hypophosphatemic osteomalacia in whom a clinical diagnosis of TIO was confirmed before surgical removal of the tumor by localizing the responsible tumor using venous sampling for FGF-23 together with magnetic resonance imaging. This combinatorial procedure would be clinically useful for sporadic cases of hypophosphatemic rickets/osteomalacia. (J Clin Endocrinol Metab 89: 3979 –3982, 2004)
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fgf 23 transgenic mice demonstrate hypophosphatemic rickets with reduced expression of sodium phosphate cotransporter type iia
Biochemical and Biophysical Research Communications, 2004Co-Authors: Takashi Shimada, Hisashi Hasegawa, Rieko Hino, Takashi Yoneya, Itaru Urakawa, Yuji Yamazaki, Seiji Fukumoto, Toshiro Fujita, Yasuhiro Takeuchi, Takeyoshi YamashitaAbstract:Fibroblast growth factor (FGF)-23 was identified as a causative factor of tumor-induced osteomalacia and also as a responsible gene for autosomal dominant hypophosphatemic rickets. To clarify the pathophysiological roles of FGF-23 in these diseases, we generated its transgenic mice. The transgenic mice expressing human FGF-23 reproduced the common clinical features of these diseases such as Hypophosphatemia probably due to increased renal phosphate wasting, inappropriately low serum 1,25-dihydroxyvitamin D level, and rachitic bone. The renal phosphate wasting in the transgenic mice was accompanied by the reduced expression of sodium phosphate cotransporter type IIa in renal proximal tubules. These results reinforce the notion that the excessive action of FGF-23 plays a causative role in the development of several hypophosphatemic rickets/osteomalacia.
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fgf 23 is a potent regulator of vitamin d metabolism and phosphate homeostasis
Journal of Bone and Mineral Research, 2003Co-Authors: Takashi Shimada, Hisashi Hasegawa, Rieko Hino, Yuji Yamazaki, Seiji Fukumoto, Toshiro Fujita, Yasuhiro Takeuchi, Kazuhiko Nakahara, Takanori Muto, Takeyoshi YamashitaAbstract:We analyzed the effects of an FGF-23 injection in vivo. FGF-23 caused a reduction in serum 1,25-dihydroxyvitamin D by altering the expressions of key enzymes for the vitamin D metabolism followed by Hypophosphatemia. This study indicates that FGF-23 is a potent regulator of the vitamin D and phosphate metabolism. Introduction: The pathophysiological contribution of FGF-23 in hypophosphatemic diseases was supported by animal studies in which the long-term administration of recombinant fibroblast growth factor-23 reproduced hypophosphatemic rickets with a low serum 1,25-dihydroxyvitamin D [1,25(OH)2D] level. However, there is no clear understanding of how FGF-23 causes these changes. Materials and Methods: To elucidate the molecular mechanisms of the FGF-23 function, we investigated the short-term effects of a single administration of recombinant FGF-23 in normal and parathyroidectmized animals. Results: An injection of recombinant FGF-23 caused a reduction in serum phosphate and 1,25(OH)2D levels. A decrease in serum phosphate was first observed 9 h after the injection and was accompanied with a reduction in renal mRNA and protein levels for the type IIa sodium-phosphate cotransporter (NaPi-2a). There was no increase in the parathyroid hormone (PTH) level throughout the experiment, and Hypophosphatemia was reproduced by FGF-23 in parathyroidectomized rats. Before this hypophosphatemic effect, the serum 1,25(OH)2D level had already descended at 3 h and reached the nadir 9 h after the administration. FGF-23 reduced renal mRNA for 25-hydroxyvitamin D-1α-hydroxylase and increased that for 25-hydroxyvitamin D-24-hydroxylase starting at 1 h. In addition, an injection of calcitriol into normal mice increased the serum FGF-23 level within 4 h. Conclusions: FGF-23 regulates NaPi-2a independently of PTH and the serum 1,25(OH)2D level by controlling renal expressions of key enzymes of the vitamin D metabolism. In conclusion, FGF-23 is a potent regulator of phosphate and vitamin D homeostasis.
Yasuhiro Takeuchi - One of the best experts on this subject based on the ideXlab platform.
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venous sampling for fibroblast growth factor 23 confirms preoperative diagnosis of tumor induced osteomalacia
The Journal of Clinical Endocrinology and Metabolism, 2004Co-Authors: Yasuhiro Takeuchi, Yuji Yamazaki, Takeyoshi Yamashita, Hisanori Suzuki, Sayoko Ogura, Rie Imai, Yoshinari Miyamoto, Hiroshi Okazaki, Kozo Nakamura, Kazuhiko NakaharaAbstract:Tumor-induced osteomalacia (TIO) is a paraneoplastic disorder characterized by Hypophosphatemia, phosphaturia, inappropriately low serum levels of 1,25-dihydroxyvitamin D for Hypophosphatemia, and skeletal undermineralization. Patients with TIO suffer from severe muscle weakness and pain. Because surgical removal of the responsible tumors is the only satisfactory treatment for TIO, identification of the tumors is clinically essential. However, because they are predominantly slow-growing neoplasms of benign mesenchymal origin, localization of the responsible tumors is often very difficult. Moreover, even if a tumor is found in a patient with hypophosphatemic osteomalacia, we have had no way to know that the tumor is actually causing the disease. Fibroblast growth factor-23 (FGF-23) was recently identified as a causative factor for TIO and was shown to induce renal phosphate wasting. We have recently shown that the circulatory FGF-23 level was high in a patient with TIO and rapidly decreased after removal of the responsible tumor. For the first time, we describe a patient with adult-onset hypophosphatemic osteomalacia in whom a clinical diagnosis of TIO was confirmed before surgical removal of the tumor by localizing the responsible tumor using venous sampling for FGF-23 together with magnetic resonance imaging. This combinatorial procedure would be clinically useful for sporadic cases of hypophosphatemic rickets/osteomalacia.
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venous sampling for fibroblast growth factor 23 confirms preoperative diagnosis of tumor induced osteomalacia
The Journal of Clinical Endocrinology and Metabolism, 2004Co-Authors: Yasuhiro Takeuchi, Yuji Yamazaki, Takeyoshi Yamashita, Hisanori Suzuki, Sayoko Ogura, Rie Imai, Yoshinari Miyamoto, Hiroshi Okazaki, Kozo Nakamura, Kazuhiko NakaharaAbstract:Tumor-induced osteomalacia (TIO) is a paraneoplastic disorder characterized by Hypophosphatemia, phosphaturia, inappropriately low serum levels of 1,25-dihydroxyvitamin D for Hypophosphatemia, and skeletal undermineralization. Patients with TIO suffer from severe muscle weakness and pain. Because surgical removal of the responsible tumors is the only satisfactory treatment for TIO, identification of the tumors is clinically essential. However, because they are predominantly slow-growing neoplasms of benign mesenchymal origin, localization of the responsible tumors is often very difficult. Moreover, even if a tumor is found in a patient with hypophosphatemic osteomalacia, we have had no way to know that the tumor is actually causing the disease. Fibroblast growth factor-23 (FGF-23) was recently identified as a causative factor for TIO and was shown to induce renal phosphate wasting. We have recently shown that the circulatory FGF-23 level was high in a patient with TIO and rapidly decreased after removal of the responsible tumor. For the first time, we describe a patient with adult-onset hypophosphatemic osteomalacia in whom a clinical diagnosis of TIO was confirmed before surgical removal of the tumor by localizing the responsible tumor using venous sampling for FGF-23 together with magnetic resonance imaging. This combinatorial procedure would be clinically useful for sporadic cases of hypophosphatemic rickets/osteomalacia. (J Clin Endocrinol Metab 89: 3979 –3982, 2004)
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fgf 23 transgenic mice demonstrate hypophosphatemic rickets with reduced expression of sodium phosphate cotransporter type iia
Biochemical and Biophysical Research Communications, 2004Co-Authors: Takashi Shimada, Hisashi Hasegawa, Rieko Hino, Takashi Yoneya, Itaru Urakawa, Yuji Yamazaki, Seiji Fukumoto, Toshiro Fujita, Yasuhiro Takeuchi, Takeyoshi YamashitaAbstract:Fibroblast growth factor (FGF)-23 was identified as a causative factor of tumor-induced osteomalacia and also as a responsible gene for autosomal dominant hypophosphatemic rickets. To clarify the pathophysiological roles of FGF-23 in these diseases, we generated its transgenic mice. The transgenic mice expressing human FGF-23 reproduced the common clinical features of these diseases such as Hypophosphatemia probably due to increased renal phosphate wasting, inappropriately low serum 1,25-dihydroxyvitamin D level, and rachitic bone. The renal phosphate wasting in the transgenic mice was accompanied by the reduced expression of sodium phosphate cotransporter type IIa in renal proximal tubules. These results reinforce the notion that the excessive action of FGF-23 plays a causative role in the development of several hypophosphatemic rickets/osteomalacia.
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fgf 23 is a potent regulator of vitamin d metabolism and phosphate homeostasis
Journal of Bone and Mineral Research, 2003Co-Authors: Takashi Shimada, Hisashi Hasegawa, Rieko Hino, Yuji Yamazaki, Seiji Fukumoto, Toshiro Fujita, Yasuhiro Takeuchi, Kazuhiko Nakahara, Takanori Muto, Takeyoshi YamashitaAbstract:We analyzed the effects of an FGF-23 injection in vivo. FGF-23 caused a reduction in serum 1,25-dihydroxyvitamin D by altering the expressions of key enzymes for the vitamin D metabolism followed by Hypophosphatemia. This study indicates that FGF-23 is a potent regulator of the vitamin D and phosphate metabolism. Introduction: The pathophysiological contribution of FGF-23 in hypophosphatemic diseases was supported by animal studies in which the long-term administration of recombinant fibroblast growth factor-23 reproduced hypophosphatemic rickets with a low serum 1,25-dihydroxyvitamin D [1,25(OH)2D] level. However, there is no clear understanding of how FGF-23 causes these changes. Materials and Methods: To elucidate the molecular mechanisms of the FGF-23 function, we investigated the short-term effects of a single administration of recombinant FGF-23 in normal and parathyroidectmized animals. Results: An injection of recombinant FGF-23 caused a reduction in serum phosphate and 1,25(OH)2D levels. A decrease in serum phosphate was first observed 9 h after the injection and was accompanied with a reduction in renal mRNA and protein levels for the type IIa sodium-phosphate cotransporter (NaPi-2a). There was no increase in the parathyroid hormone (PTH) level throughout the experiment, and Hypophosphatemia was reproduced by FGF-23 in parathyroidectomized rats. Before this hypophosphatemic effect, the serum 1,25(OH)2D level had already descended at 3 h and reached the nadir 9 h after the administration. FGF-23 reduced renal mRNA for 25-hydroxyvitamin D-1α-hydroxylase and increased that for 25-hydroxyvitamin D-24-hydroxylase starting at 1 h. In addition, an injection of calcitriol into normal mice increased the serum FGF-23 level within 4 h. Conclusions: FGF-23 regulates NaPi-2a independently of PTH and the serum 1,25(OH)2D level by controlling renal expressions of key enzymes of the vitamin D metabolism. In conclusion, FGF-23 is a potent regulator of phosphate and vitamin D homeostasis.
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fgf 23 is a potent regulator of vitamin d metabolism and phosphate homeostasis
Journal of Bone and Mineral Research, 2003Co-Authors: Takashi Shimada, Hisashi Hasegawa, Rieko Hino, Yuji Yamazaki, Seiji Fukumoto, Toshiro Fujita, Yasuhiro Takeuchi, Kazuhiko Nakahara, Takanori Muto, Takeyoshi YamashitaAbstract:UNLABELLED: We analyzed the effects of an FGF-23 injection in vivo. FGF-23 caused a reduction in serum 1,25-dihydroxyvitamin D by altering the expressions of key enzymes for the vitamin D metabolism followed by Hypophosphatemia. This study indicates that FGF-23 is a potent regulator of the vitamin D and phosphate metabolism. INTRODUCTION: The pathophysiological contribution of FGF-23 in hypophosphatemic diseases was supported by animal studies in which the long-term administration of recombinant fibroblast growth factor-23 reproduced hypophosphatemic rickets with a low serum 1,25-dihydroxyvitamin D [1,25(OH)2D] level. However, there is no clear understanding of how FGF-23 causes these changes. MATERIALS AND METHODS: To elucidate the molecular mechanisms of the FGF-23 function, we investigated the short-term effects of a single administration of recombinant FGF-23 in normal and parathyroidectmized animals. RESULTS: An injection of recombinant FGF-23 caused a reduction in serum phosphate and 1,25(OH)2D levels. A decrease in serum phosphate was first observed 9 h after the injection and was accompanied with a reduction in renal mRNA and protein levels for the type IIa sodium-phosphate cotransporter (NaPi-2a). There was no increase in the parathyroid hormone (PTH) level throughout the experiment, and Hypophosphatemia was reproduced by FGF-23 in parathyroidectomized rats. Before this hypophosphatemic effect, the serum 1,25(OH)2D level had already descended at 3 h and reached the nadir 9 h after the administration. FGF-23 reduced renal mRNA for 25-hydroxyvitamin D-1alpha-hydroxylase and increased that for 25-hydroxyvitamin D-24-hydroxylase starting at 1 h. In addition, an injection of calcitriol into normal mice increased the serum FGF-23 level within 4 h. CONCLUSIONS: FGF-23 regulates NaPi-2a independently of PTH and the serum 1,25(OH)2D level by controlling renal expressions of key enzymes of the vitamin D metabolism. In conclusion, FGF-23 is a potent regulator of phosphate and vitamin D homeostasis.