Department of Bone and Mineral Research

Department of Bone and Mineral Research

We aim to contribute in the field of bone and mineral research and to develop new techniques for diagnosis and treatment of skeletal disorders and growth retardation.

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Investigation of Regulatory Mechanism for Skeletal Development and Pathogenesis of Growth Retardation
  1. Studies on the Mechanisms for Development and Homeostasis of Skeletons
    In vertebrates, most of the skeleton is formed through endochondral ossification. Endochondral bone formation is a complex process involving the mesenchymal condensation of undifferentiated cells, the proliferation of chondrocytes and differentiation into hypertrophic chondrocytes, followed by mineralization. This process is tightly regulated by various factors including transcription factors, soluble mediators, extracellular matrix, and cell-cell and cell-matrix interactions. Defects of these factors often lead to disturbance of skeletal growth. In this project, we aim to clarify the regulatory mechanisms underlying the development and homeostasis of skeletons and contribute to the healthy growth in fetuses and children.
  2. Analyses of the Pathogenesis of Genetic Skeletal Disorders and Development of New Therapeutic Approaches
    Genetic skeletal disorders arise through disturbances in the complex processes of skeletal development, growth and homeostasis, and include more than 400 conditions. In addition to the abnormality in skeletal systems, some of them are associated with life-threatening complications such as respiratory problems. Although the genetic skeletal disorders have long been considered untreatable, understanding their molecular basis may enable accurate diagnosis and effective treatments.We are attempting to clarify the molecular pathogenesis of these diseases and develop new therapeutic approaches.
Elucidation of the Molecular Basis for Phosphate Sensing and Metabolism

Phosphorus is involved in various biological processes including membrane integrity, maintenance and inheritance of genetic materials, energy metabolism, intracellular signaling and skeletal mineralization. In addition, accumulating evidences have indicated that alteration in the levels of extracellular inorganic phosphate (Pi) itself triggers signaling to regulate gene expression and cellular functions in some cell types. Fibroblast growth factor 23 (FGF23), which plays a central role in Pi homeostasis, is produced by osteocytes. Osteocytes express other molecules involved in Pi metabolism also, including Dmp1 and Phex. In this project, we are investigating the mechanisms by which the Pi availability is sensed and the genes are regulated to maintain Pi homeostasis.

Studies on the uterine environment and genetic factors for
embryonic implantation and development

Human oocytes fertilized in fallopian tubes are transported and implanted at the endometrium. For around ten months, implanted embryos develop and grow in utero with the support of exchanges of gases and nutrients between mothers and fetuses until birth. Many mysteries about the developmental processes of fetuses and the necessary intrauterine environment are remained to be elucidated. Why do major causes of infertility such as implantation failure and early miscarriage take place? As about 5% of newborns have some congenital malformations such as neural tube defects or heart diseases, mechanisms for the development of these congenital anomalies are also still unclear. To dissect the intrauterine environment necessary for embryo implantation and subsequent development and identify genetic factors causing congenital diseases, we are exploiting mice as an experimental model animal. Mice are powerful tools in which both reverse and forward genetics can be readily applicable. As a genetic approach for congenital malformations, we are generating several mouse models, in which human disease-related genes are mutated. As for the uterine environment, we are analyzing mechanical factors of the uterus such as smooth muscle contractions and endometrial stiffness utilizing biophysical techniques in combination with in vitro culture of embryos. These approaches can accelerate basic biological research on embryonic development as well as the evaluation of therapeutics by allowing us to dissect functions of genetic pathways and intrauterine properties for embryo implantation and development.


Head Toshimi Michigami, M.D., Ph.D.
Chief Scientist
Research Fellow Miwa Yamazaki, Ph.D.
Technical Assistant Kanako Tachikawa
Saori Kinoshita
PhD Course Student Shinsuke Onuma, M.D.



Nakanishi T, Yamazaki M, Tachikawa K, Ueta A, Kawai M, Ozono K, Michigami T. Complex intrinsic abnormalities in osteoblast lineage cells of X-linked hypophosphatemia: analysis of human iPS cell models generated by CRISPR/Cas9-mediated gene ablation. Bone. 181: 117044, 2024


Michigami T. Paracrine and endocrine functions of osteocytes. Clin Pediatr Endocrinol. 32: 1-10, 2023

Tachikawa K, Yamazaki M, Michigami T. A unique case of childhood hypophosphatasia caused by a novel heterozygous 51-bp in-frame deletion in the ALPL gene. Clin Pediatr Endocrinol. 32:180–187, 2023

Yamagishi H, Monden Y, Michigami T, Tachikawa K, Osaka H, Nozaki Y, Tajima T. A case of osteopathia striata with cranial sclerosis with facial nerve palsies. Pediatr Int. 65: e15648, 2023

Hidaka N, Murata H, Tachikawa K, Osaki K, Sekiyama T, Kinoshita Y, Kato H, Hoshino Y, Kimura S, Sunouchi T, Watanabe S, Nangaku M, Makita N, Michigami T, Ito N. The effect of Asfotase Alfa on plasma and urine pyrophosphate levels and pseudofractures in a patient with adult-onset hypophosphatasia. JBMR Plus. 7: e10842, 2023


Yamazaki M, Michigami T. Osteocytes and the pathogenesis of hypophosphatemic rickets. Front Endocrinol (Lausanne). 13:1005189, 2022

Kamiya Y, Matsushita M, Mishima K, Ohkawara B, Michigami T, Imanaga S, Ohno K, Kitoh H. Meclozine ameliorates bone mineralization and growth plate structure in a mouse model of X-linked hypophosphatemia. Exp Ther Med. 25:39, 2022

Michigami T. Roles of osteocytes in phosphate metabolism. Front Endocrinol (Lausanne), Jul 15, 13:967774, 2022

Onuma S, Kinoshita S, Shimba S, Ozono K, Michigami T, Kawai M. The lack of Bmal1, a core clock gene, in the intestine decreases glucose absorption in mice. Endocrinology. 163: bqac119, 2022

Michigami T. Advances in understanding of phosphate homeostasis and related disorders. Endocr J. 69: 881-896, 2022

Nakanishi T, Michigami T. Pathogenesis of FGF23-related hypophosphatemic diseases including X-linked hypophosphatemia. Endocrines. 3: 303-316, 2022

Yamamura-Miyazaki N, Michigami T, Ozono K, Yamamoto K, Hasuike Y. Factors associated with 1-year changes in serum fibroblast growth factor 23 levels in pediatric patients with chronic kidney disease. Clin Exp Nephrol. 26: 1014-1021, 2022

Michigami T, Tachikawa K, Yamazaki M, Nakanishi T, Kawai M, Ozono K. Growth-related skeletal changes and alterations in phosphate metabolism. Bone. 161: 116430, 2022

Michigami T, Yamazaki M, Razzaque MS. Extracellular phosphate, inflammation and cytotoxicity. Ann Exp Med Biol. 1362: 15-25, 2022

Kawai M. Disruption of the circadian rhythms and its relationship with pediatric obesity. Pediatr Int. 64: e14992, 2022

Nakano S, Yamamura-Miyazaki N, Michigami T, Yazawa K, Yanagihara I, Yamamoto K. A case of a preschool child with a successful kidney transplant following a long-term administration of antibiotics to treat peritoneal dialysis-related ESI/peritonitis by Mycobacterium abscessus. CEN Cas Rep. 11: 408-411, 2022


Ishihara Y, Ohata Y, Takeyari S, Kitaoka T, Fujiwara M, Nakano Y, Yamamoto K, Yamada C, Yamamoto K, Michigami T, Mabe H, Yamaguchi T, Matsui K, Tamada I, Namba N, Yamamoto A, Etoh J, Kawaguchi A, Kosugi R, Ozono K, Kubota T. Genotype-phenotype analysis and assessment of the importance of the zinc-binding site in PHEX in Japanese patients with X-linked hypophosphatemic rickets using 3D structure modeling. Bone, 135: 116135, 2021

Yamazaki M, Kawai M, Kinoshita S, Tachikawa K, Nakanishi T, Ozono K, Michigami T. Clonal osteoblastic cell lines with CRISPR/Cas9-mediated ablation of Pit1 or Pit2 show enhanced mineralization despite reduced osteogenic gene expression. Bone, 151: 116036, 2021

Kato M, Michigami T, Tachikawa K, Kato M, Yabe I, Shimizu T, Asaka T, Kitagawa Y, Atsumi T. Novel mutation in the ALPL gene with a dominant negative effect in a Japanese family. J Bone Miner Metab, 39: 804­809, 2021

Mukai M, Yamamoto T, Takeyari S, Ohata Y, Kitaoka T, Kubota T, Yamamoto K, Kijima E, Hasegawa Y, Michigami T, Ozono K. Alkaline phosphatase in pediatric patients with genu varum caused vitamin D-deficient rickets. Endocr J, 68: 807­815, 2021


Kawai M, Kinoshita S, Ozono K, Michigami T. Lack of PTEN in osteocytes increases circulating phosphate concentrations by decreasing intact fibroblast growth factor 23 levels. Sci Rep 10: 21501, 2020

Kubota T, Fukumoto S, Cheong HI, MIchigami T, Namba N, Ito N, Tokunaga S, Gibbs Y, Ozono K. Long-term outcomes for Asian patients with X-linked hypophosphataemia: rationale and design of the SUNFLOWER longitudinal, observational cohort study. BMJ Open, 10: e036367, 2020

Michigami T, Tachikawa K, Yamazaki M, Kawai M, Kubota T, Ozono K. Hypophosphatasia in Japan: ALPL mutation analysis in 98 unrelated patients. Calcif Tissue Int, 106:221–231, 2020

Michigami T, Ohata Y, Fujiwara M, Mochizuki H, Adachi M, Kitaoka T, Kubota T, Sawai H, Namba N, Hasegawa K, Fujiwara I, Ozono K. Clinical Practice Guidelines for Hypophosphatasia. Clin Pediatr Endocrinol, 29: 9–24, 2020

Kubota T, Adachi M, Kitaoka T, Hasegawa K, Ohata Y, Fujiwara M, Michigami T, Mochizuki H, Ozono K. Clinical Practice Guidelines for Achondroplasia. Clin Pediatr Endocrinol, 29: 25–24, 2020

Takaki N, Mori J, Matsuo S, Osamura T, Michigami T. Cleidocranial dysplasia with growth hormone deficiency: a case report. BMC Pediatr,20:19, 2020

Yamamura-Miyazaki, Michigami T, Satomura K, Urushihara M, Kagami S, Yamamoto K. Reduction in urinary angiotensinogen levels and improvement of proteinuria by renin-angiotensin system blockade in pediatric chronic kidney disease patients with very low birth weight. Pediatr Nephrol, 35: 1307–1314, 2020

Michigami T. Skeletal mineralization: mechanisms and diseases. Ann Pediatr Endocrinol Metab, 24:213–219, 2020


Kawai M, Kinoshita S, Yamazaki M, Yamamoto K, Rosen CJ, Shimba S, Ozono K, Michigami T. Intestinal clock system regulates skeletal homeostasis. JCI Insight. Mar 7:4(5). pii121798, 2019.

Rassie K, Dray M, Michigami T, Cundy T. Bisphosphonate use and fractures in adults with hypophosphtasia. JBMR Plus, Aug 26:3 (10). e10223, 2019

Michigami T, Ozono K. Roles of phosphate in skeleton. Front Endocrinol, Mar 26, 10:180, 2019

Ohata Y, Takeyari S, Nakano Y, Kitaoka T, Nakayama H, Bizaoui V, Yamamoto K, Miyata K, Yamamoto K, Fujiwara M, Kubotaa T, Michigami T, Yamamoto K, Yamamoto T, Namba N, Ebina K, Yoshikawa H, Ozono K. Comprehensive genetic analyses using targeted next-generation sequencing and genotype-phenotype correlations in 53 Japanese patients with osteogenesis imperfecta. Osteoporosis Int, 30:2333–2342, 2019

Okawa R, Kokomoto K, Kitaoka T, Kubota T, Watanabe A, Taketani T, Michigami T, Ozono K, Nakano K. Japanese nationwide survey of hypophosphtasia reveals prominent differences in genetic and dental findings between odonto and non-odonto types. PLoS One, Oct 10:14(10). e0222931, 2019

Ishiguro T, Sugiyama Y, Ueda K, Muramatsu Y, Tsuda H, Kotani T, Michigami T, Tachikawa K, Akiyama T, Hayakawa M. Brain Dev,41:721–725, 2019.


Yamamoto K, Kawai M, Yamazaki M, Tachikawa K, Kubota T, Ozono K, Michigami T. CREB activation in hypertrophic chondrocytes is involved in the skeletal overgrowth in epiphyseal chondrodysplasia Miura type caused by activating mutations of natriuretic peptide receptor B. Hum Mol Genet. 2018 Dec 13, [E-pub ahead of print]

Hasegawa Y, Kawai M, Bessho K, Yasuda K, Ueno T, Satomura Y, Konishi A, Kimura T, Ikeda K, Tachibana M, Miyoshi Y, Michigami T, Kondou H, Ozono K. CYP7A1 expression in hepatocytes is retained with upregulated fibroblast growth factor 19 in pediatric biliary atresia. Hepatol Res. 2018 Aug 29, [E-pub ahead of print]

Michigami T, Kawai M, Yamazaki M, Ozono K. Phosphate as a signaling molecule and its sensing mechanism. Physiol Rev. 98:2317–2348, 2018

Kubota T, Nakayama H, Kitaoka T, Nakamura Y, Fukumoto S, Fujiwara I, Hasegawa Y, Ihara K, Kitanaka S, Koyama S, Kusuda S, Mizuno H, Nagasaki K, Oba K, Sakamoto Y, Takubo N, Shimizu Y, Tanahashi Y, Hasegawa K, Tsukahara H, Yorifuji T, Michigami T, Ozono K. Incidence rate and characteristics of symptomatic vitamin D deficiency in children: a nationwide survey in Japan. Endocr J. 65:593–599, 2018

Akiyama T, Kubota T, Ozono K, Michigami T, Kobayashi D, Takeyari S, Sugiyama Y, Noda M, Harada D, Namba N, Suzuki A, Utoyama M, Kitanaka S, Uematsu M, Mitani Y, Matsunami K, Takishima S, Ogawa E, Kobayashi K. Pyridoxal 5-phosphate and related metabolites in hypophosphatasia: Effects of enzyme replacement therapy. Mol Genet Metab. 125:174–180, 2018

Oyachi M, Harada D, Sakamoto N, Ueyama K, Kondo K, Kishimoto K, Izui M, Nagamatsu Y, Kashiwagi H, Yamamuro M, Tamura M, Kikuchi S, Akiyama T, Michigami T, Seino Y, Namba N. A case of perinatal hypophosphatasia with a novel mutation in the ALPL gene: clinical course and review of the literature. Clin Pediatr Endocrinol. 27:179–186, 2018

Ikenoue S, Miyakoshi K, Ishii T, Sato Y, Otani T, Akiba Y, Kasuga Y, Ochiai D, Matsumoto T, Ichihashi Y, Matsuzaki Y, Tachikawa K, Michigami T, Nishimura G, Ikeda K, Hasegawa T, Tanaka M. Discordant fetal phenotype of hypophosphatasia in two siblings. Am J Med Genet A. 176:171–174, 2018


Watanabe R, Fujita N, Sato Y, Kobayashi T, Morita M, Oike T, Miyamoto K, Kuro-O M, Michigami T, Fukumoto S, Tsuji T, Toyama Y, Nakamura M, Matsumoto M, Miyamoto T. Enpp1 is an anti-aging factor that regulates Klotho under phosphate overload conditions. Sci Rep. 7:7886, 2017

Kitaoka T, Tajima T, Nagasaki K, Kikuchi T, Yamamoto K, Michigami T, Okada S, Fujiwara I, Kokaji M, Mochizuki H, Ogata T, Tatebayashi K, Watanabe A, Yatsuga S, Kubota T, Ozono K. Safety and efficacy of treatment with asfotase alfa in patients with hypophosphatasia: Results from a Japanese clinical trial. Clin Endocrinol (Oxf). 87:10–19, 2017

Nishino J, Yamazaki M, Kawai M, Tachikawa K, Yamamoto K, Miyagawa K, Kogo M, Ozono K, Michigami T. Extracellular phosphate induces the expression of dentin matrix protein 1 through the FGF receptor in osteoblasts. J Cell Biochem. 118:1151–1163, 2017

Yamamura-Miyazaki N, Yamamoto K, Fujiwara K, Santo Y, Michigami T, Kitajima H, Satomura K. Risk factors associated with a decreased estimated glomerular filtration rate based on cystatin C levels in school-age children with extremely low birthweight. Nephrology (Carlton). 22:463–469, 2017

Kajita S, Yamamoto T, Tsugawa N, Nakayama H, Kubota T, Michigami T, Ozono K. Serum calcitriol levels in a patient with X-linked hypophosphatemia complicated by autosomal dominant polycystic kidney disease. CEN Case Rep. 6:29–35, 2017

Okazaki R, Ozono K, Fukumoto S, Inoue D, Yamauchi M, Minagawa M, Michigami T, Takeuchi Y, Matsumoto T, Sugimoto T. Assessment criteria for vitamin D deficiency/insufficiency in Japan: proposal by an expert panel supported by the Research Program of Intractable Diseases, Ministry of Health, Labour and Welfare, Japan, the Japanese Society for Bone and Mineral Research and the Japan Endocrine Society [Opinion]. Endocr J. 64:1–6, 2017

Okazaki R, Ozono K, Fukumoto S, Inoue D, Yamauchi M, Minagawa M, Michigami T, Takeuchi Y, Matsumoto T, Sugimoto T. Assessment criteria for vitamin D deficiency/insufficiency in Japan: proposal by an expert panel supported by the Research Program of Intractable Diseases, Ministry of Health, Labour and Welfare, Japan, the Japanese Society for Bone and Mineral Research and the Japan Endocrine Society [Opinion]. J Bone Miner Metab. 35:1–5, 2017


Kawai M, Kinoshita S, Ozono K, Michigami T. Inorganic phosphate activates the AKT/mTORC pathway and shortens the life span of an a-Klotho-deficient model. J Am Soc Nephrol. 27:2810–2824, 2016

Ohata Y, Ozono K, Michigami T. Current concepts in perinatal mineral metabolism. Clin Pediatr Endocrinol. 25:9–17, 2016

Fujiwara M, Kubota T, Wang W, Ohata Y, Miura K, Kitaoka T, Okuzaki D, Namba N, Michigami T, Kitabatake Y, Ozono K. Successful induction of sclerostin in human derived fibroblasts by 4 transcription factors and its regulation by parathyroid hormone, hypoxia, and prostaglandin E2. Bone. 85:91–98, 2016

Munns CF, Shaw N, Kiely M, Specker BL, Thacher TD, Ozono K, Michigami T, Tiosano D, Mughal MZ, Mäkitie O, Ramos-Abad L, Ward L, DiMeglio LA, Atapattu N, Cassinelli H, Braegger C, Pettifor JM, Seth A, Idris HW, Bhatia V, Fu J, Goldberg G, Sävendahl L, Khadgawat R, Pludowski P, Maddock J, Hyppönen E, Oduwole A, Frew E, Aguiar M, Tulchinsky T, Butler G, Högler W. Global consensus recommendations on prevention and management of nutritional rickets. J Clin Endocrinol Metab. 101:394–415, 2016

Munns CF, Shaw N, Kiely M, Specker BL, Thacher TD, Ozono K, Michigami T, Tiosano D, Mughal MZ, Mäkitie O, Ramos-Abad L, Ward L, DiMeglio LA, Atapattu N, Cassinelli H, Braegger C, Pettifor JM, Seth A, Idris HW, Bhatia V, Fu J, Goldberg G, Sävendahl L, Khadgawat R, Pludowski P, Maddock J, Hyppönen E, Oduwole A, Frew E, Aguiar M, Tulchinsky T, Butler G, Högler W. Global consensus recommendations on prevention and management of nutritional rickets. Horm Res Paediatr. 85:83–106, 2016

Okazaki Y, Kitajima H, Mochizuki N, Kitaoka T, Michigami T, Ozono K. Lethal hypophosphatasia successfully treated with enzyme replacement from day 1 after birth. Eur J Pediatr. 175:433–437, 2016


Yamazaki M, Kawai M, Miyagawa K, Ohata Y, Tachikawa K, Kinoshita S, Nishino J, Ozono K, Michigami T. IL-1-induced acute bone resorption facilitates the secretion of fibroblast growth factor 23 into the circulation. J Bone Miner Metab, 33:342–354, 2015

Cundy T, Michigami T, Tachikawa K, Dray M, Collins JF, Raschalis EP, Gamsjaeger S, Roschger A. Reversible deterioration in hypophosphatasia caused by renal failure with bisphosphonate treatment. J Bone Miner Res. 30:1726–1732, 2015

Endo I, Fukumoto S, Ozono K, Namba N, Inoue D, Okazaki R, Yamauchi M, Sugimoto T, Minagawa M, Michigami T, Nagai M, Matsumoto T. Nationwide survey of fibroblast growth factor 23 (FGF23)-related hypophosphtaemic diseases in Japan: prevalemce, biochemical data and treatment. Endocr J. 62:811-816, 2015

Fukumoto S, Ozono K, Michigami T, Minagawa M, Okazaki R, Sugimoto T, Takeuchi Y, Matsumoto T. Pathogenesis and diagnostic criteria for rickets and osteomalacia-Proposal by an expert panel supported by Ministry of Health, Labour and Welfare, Japan. The Japanese Society for Bone and Mineral Ressearch and The Japan Endocrine Society. Endocr J.62:665-671, 2015

Fukumoto S, Ozono K, Michigami T, Minagawa M, Okazaki R, Sugimoto T, Takeuchi Y, Matsumoto T. Pathogenesis and diagnostic criteria for rickets and osteomalacia-Proposal by an expert panel supported by Ministry of Health, Labour and Welfare, Japan. The Japanese Society for Bone and Mineral Ressearch and The Japan Endocrine Society. J Bone Miner Metab.33:467-473, 2015


Miyagawa K, Yamazaki M, Kawai M, Nishino J, Koshimizu T, Ohata Y, Tachikawa K, Mikuni-Takagaki Y, Kogo M, Ozono K, Michigami T. Dysregulated gene expression in the primary osteoblasts and osteocytes isolated from hypophosphatemic Hyp mice. PLoS One 9:e93840, 2014

Michigami T. Current understanding on the molecular basis of chondrogenesis. Clin Pediatr Endocrinol 23:1-8, 2014

Ohata Y, Yamazaki M, Kawai M, Tsugawa N, Tachikawa K, Koinuma T, Miyagawa K, Kimoto A, Nakayama M, Namba N, Yamamoto H, Okano T, Ozono K, Michigami T. Elevated fibroblast growth factor 23 exerts its effects on placenta and regulates vitamin D metabolism in pregnancy of Hyp mice. J Bone Miner Res. 29:1627-1638, 2014

Kawai M, Kinoshita S, Shimba S, Ozono K, Michigami T. Sympathetic activation induces skeletal Fgf23 expression in a circadian rhythm dependent manner. J Biol Chem, 289:1457-1466, 2014

Miura K, Kim OH, Lee HR, Namba N, Michigami T, Yoo WJ, Choi IH, Ozono K, Cho TJ. Overgrowth syndrome associated with a gain-of-function mutation of the natriuretic peptide receptor 2 (NPR2) gene. Am J Med Genet A. 164A:156-163, 2014

Matsushita M, Kitoh H, Michigami T, Tachikawa K, Ishiguro N. Benign prenatal hypophosphatasia: a treatable disease not to be missed. Pediatr Radiol 44:340-343, 2014

Takeyari S, Yamamoto T, Kinoshita Y, Fukumoto S, Glorieux FH, Michigami T, Hasegawa K, Kitaoka T, Kubota T, Imanishi Y, Shimotsuji T, Ozono K. Hypophosphatemic osteomalacaia 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. 67C:56-62, 2014

Kuroyanagi Y, Kawasaki H, Noda Y, Ohmachi T, Sekiya S, Yoshimura K, Ohe C, Michigami T, Ozono K, Kaneko K. A fetal case of infantile malignant osteopetrosis complicated by pulmonary arterial hypertention after hematopoietic stem cell transplantation. Tohoku J Exp Med. 234:309–312, 2014


Robinson JW, Dickey DM, Miura K, Michigami T, Ozono K, Potter LR. A human skeletal overgrowth mutation increases maximal velocity and blocks desensitization of guanylyl cyclase-B. Bone. 56:375-382. 2013

Michigami T. Regulatory mechanisms for the development of growth plate cartilage. Cell Mol Life Sci. 70:4213-4221, 2013

Michigami T. Extracellular phosphate as a signaling molecule. Contrib Nephrol. 180:14-24, 2013

Kondou H, Kawai M, Tachikawa K, Kimoto A, Yamagata M, Koinuma T, Yamazaki M, Nakayama M, Mushiake S, Ozono K, Michigami T. Sodium-coupled neutral amino acid transporter 4 functions as a regulator of protein synthesis during liver development. Hepatol Res. 43:4213-4221, 2013

Wada K, Harada D, Michigami T, Tachikawa K, Nakano Y, Kashiwagi H, Yamashita S, Sano T, Seino Y. A case of autosomal dominant osteopetrosis type II with a novel TCIRG1 gene mutation. J Pediatr Endocrinol Metab. 26:575-577, 2013

Matsui I, Hamano T, Mikami S, Inoue K, Shimomura A, Nagasawa Y, Michigami T, Ohnishi T, Fujii N, Nakano C, Kusunoki Y, Kitamura H, Iwatani H, Takabatake Y, Kaimori JY, Matsuba G, Okoshi K, Kimura-Suda H, Tsubakihara Y, Rakugi H, Isaka Y. Retention of fetuin-A in renal tubular lumen protects the kidney from nephrocalcinosis in rats. Am J Physiol Renal Physiol. 304:F751-60, 2013

Kawai M, Kinoshita S, Kimoto A, Hasegawa Y, Miyagawa K, Yamazaki M, Ohata Y, Ozono K, Michigami T. FGF23 suppresses chondrocyte proliferation in the presence of soluble -Klotho both in vivo and in vitro. J Biol Chem. 288:2414-2427, 2013


Haraikawa M, Tanabe R, Sogabe N, Sugimoto A, Kawamura Y, Michigami T, Hosoi T, Goseki-Sone M. A study of the association between serum bone-specific alkaline phosphatase and serum phosphorus concentration or dietary phosphorus intake. J Nutr Sci Vitaminol (Tokyo). 58:442-445, 2012

Ozono K, Namba N, Kubota T, Kitaoka T, Miura K, Ohata Y, Fujiwara M, Miyoshi Y, Michigami T. Pediatric aspects of skeletal dysplasia. Pediatr Endocrinol Rev. 10 Suppl 1:35-43, 2012

Miura K, Namba N, Fujiwara M, Ohata Y, Ishida H, Kitaoka T, Kubota T, Hirai H, Higuchi C, Tsumaki N, Yoshikawa H, Sakai N, Michigami T, Ozono K. An overgrowth disorder associated with excessive production of cGMP due to a gain-of-function mutation of the natriuretic peptide receptor 2 gene. PLoS One. 7:e42180, 2012

Onodera A, Tani M, Michigami T, Yamagata M, Min KS, Tanaka K, Nakanishi T, Kimura T, Itoh N. Role of megalin and the soluble form of its ligand RAP in Cd-metallothionein endocytosis and Cd-metallothionein-induced nephrotoxicity in vivo. Toxicol Lett. 212: 91-96, 2012

Koshimizu T, Kawai M, Kondou H, Tachikawa K, Sakai N, Ozono K, Michigami T. Vinculin functions as regulator of chondrogenesis. J Biol Chem. 287:15760-15775, 2012


Ohata Y, Arahori H, Namba N, Kitaoka T, Hirai H, Wada K, Nakayama M, Michigami T, Imura A, Nabeshima YI, Yamazaki Y, Ozono K. Circulating levels of soluble -Klotho are markedly elevated in human umbilical cord blood. J Clin Endocrinol Metab. 96:E943-947, 2011

Kawai M, Breggia AC, Demambro VE, Shen X, Canalis E, Bouxsein ML, Beamer WG, Clemmons DR, Rosen CJ. The Heparin-binding domain of IGFBP-2 has insulin-like growth factor binding-independent biologic activity in the growing skeleton. J Biol Chem. 286:14670-14680, 2011

Ozono K, Michigami T. Hypophosphatasia now draws more attention of both clinicians and researchers: a commentary on Prevalence of c.1559delT in ALPL, a common mutation resulting in the perinatal (lethal) form of hypophosphatasias in Japanese and effects of the mutation on heterozygous carriers. J Hum Genet. 56:174-176, 2011

Kawai M, Modder U, Khosla S, Rosen CJ. Emerging therapeutic opportunities for skeletal restoration. Nat Rev Drug Discov. 10:141-156, 2011

Sugita A, Kawai S, Hayashibara T, Amano A, Ooshima T, Michigami T, Yoshikawa H, Yoneda T. Cellular ATP synthesis mediated by type Ⅲ sodium-dependent phosphate transporter Pit-1 is critical to chondrogenesis. J Biol Chem. 286:3094-3103, 2011


Yamazaki M, Ozono K, Okada T, Tachikawa K, Kondou H, Ohata Y, Michigami T. Both FGF23 and extracellular phosphate activate Raf/MEK/ERK pathway via FGF receptors in HEK293 cells. J Cell Biochem. 111:1210-1221, 2010

Kimata M, Michigami T*, Tachikawa K, Okada T, Koshimizu T, Yamazaki M, Kogo M, Ozono K. Signaling of inorganic extracellular phosphate up-regulates cyclin D1 expression in proliferating chondrocytes via the type III Na+/Pi cotransporter Pit-1 and Raf/MEK/ERK pathway.
Bone. 47:938-947,2010 (*Corresponding author)

Kubota T, Michigami T, Ozono K. Wnt signaling in bone. Clin Pediatr Endocrinol. 19:49-56, 2010

Nakamura-Utsunomiya A, Okada S, Hara K, Miyagawa S, Takeda K, Fukuhara R, Nakata Y, Hayashidani M, Tachikawa K, Michigami T, Ozono K, Kobayashi M. Clinical characteristics of perinatal lethal hypophosphatasia: A report of 6 cases. Clin Pediatr Endocrinol. 19:7-13, 2010


Ohata Y, Yamamoto T, Mori I, Kikuchi T, Michigami T, Imanishi Y, Satomura K, Ida S, Ozono K. Severe arterial hypertension: a possible complication of McCune-Albright syndrome. Eur J Pediatr. 168:871-876, 2009

Matsui Y, Michigami T, Tachikawa K, Yamazaki M, Kawabata H, Nishimura G. Czech dysplasia occurring in a Japanese family. Am J Med Genet(A). 149A:2285-2289, 2009

Kubota T, Michigami T, Ozono K. Wnt signaling in bone metabolism. J Bone Miner Metab. 27:265-271, 2009

Miyauchi Y, Sakaguchi N, Okada T, Makishima M, Ozono K, Michigami T. Oncogenic nucleoporin CAN/Nup214 interacts with vitamin D receptor and modulates its function. J Cell Biochem. 106:1090-1101, 2009


Fukumoto S, Namba N, Ozono K, Yamauchi M, Sugimoto T, Michigami T, Tanaka H, Inoue D, Minagawa M, Endo I, Matsumoto T. Causes and differential diagnosis of hypocalcemia-recommendation proposed by expert panel supported by ministry of health, labour and welfare, Japan-. Endocr J. 55:787-794, 2008

Kubota T, Michigami T, Sakaguchi N, Kokubu C, Suzuki A, Namba N, Sakai N, Nakajima S, Imai K, Ozono K. Lrp6 hypomorphic mutation affects bone mass through bone resorption in mice and impairs interaction with Mesd. J Bone Miner Res. 23:1661-1671, 2008

Endo I, Fukumoto S, Ozono K, Namba N, Tanaka H, Inoue D, Minagawa M, Sugimoto T, Yamauchi M, Michigami T, Matsumoto T. Clinical usefulness of measurement of fibroblast growth factor 23 (FGF23) in hypophosphatemic patients. Proposal of diagnostic criteria using FGF23 measurement. Bone. 42:1235-1239, 2008

Suzuki A, Ozono K, Kubota T, Kondou H, Tachikawa K, Michigami T. PTH/cAMP/PKA signaling facilitates canonical Wnt signaling via inactivation of glycogen synthase kinase-3β in osteoblastic Saos-2 cells. J Cell Biochem. 104:304-317, 2008


Kawai M, Mushiake S, Bessho K, Murakami M, Kokubu C, Michigami T, Ozono K. Wnt/Lrp/β-catenin signaling suppresses adipogenesis by inhibiting mutual activation of PPARγ and C/EBPα. Biochem Biophys Res Commun. 363:276-282, 2007

Uchihashi T, Kimata M, Tachikawa K, Koshimizu T, Okada T, Ihara-Watanabe M, Sakai N, Kogo M, Ozono K, Michigami T. Involvement of nuclear factor I transcription/replication factor in the early stage of chondrocytic differentiation. Bone.41:1025-1035, 2007

Yamamoto T, Michigami T, Aranami F, Segawa H, Yoh K, Nakajima S, Miyamoto KI, Ozono K. Hereditary hypophosphatemic rickets with hypercalciuria: a study for the phosphate transporter gene IIc and osteoblastic function. J Bone Miner Metab. 25:407-413, 2007


Ozono K, Michigami T, Namba N, Nakajima S, Yamamoto T. Molecular bases of diseases characterized by hypophosphatemia and phosphaturia: New understanding. Clin Pediatr Endocrinol. 15:129-135, 2006

Yamazaki M, Suzuki A, Ozono K, Michigami T. G-protein stimulatory alpha subunit is involved in osteogenic activity in osteoblastic cell line SaOS-2 cells. Clin Pediatr Endocrinol. 15:65-72, 2006

Miyoshi Y, Santo Y, Tachikawa K, Namba N, Hirai H, Mushiake S, Nakajima S, Michigami T, Ozono K. Lack of puberty despite elevated estradiol in a 46,XY phenotypic female with Frasier symdrome. Endocr J. 53:371-376, 2006

Goto T, Matsui Y, Fernandes RJ, Hanson DA, KuboT, Yukata K, Michigami T, Komori T, Fujita T, Yang L, Eyre DR, Yasui N. Sp1 family of transcription factors regulates the human 2(XI) collagen gene (COL11A2) in Saos-2 osteoblastic cells. J Bone Miner Res. 21:661-673, 2006


Miyauchi Y, Michigami T*, Sakaguchi N, Sekimoto T, Yoneda Y, Pike JW, Yamagata M, Ozono K. Importin 4 is responsible for ligand-independent nuclear translocation of vitamin D receptor. J Biol Chem. 280:40901-40908, 2005 (*corresponding author)

Yamagata M, Ozono K, Hashimoto Y, Miyauchi Y, Kondou H, Michigami T. Intraperitoneal administration of recombinant receptor-associated protein causes phosphaturia via an alteration in subcellular distribution of the renal sodium phosphate co-transporter. J Am Soc Nephrol. 16:2338-2345, 2005

Michigami T, Uchihashi T, Suzuki A, Tachikawa K, Nakajima S, Ozono K. Common mutations F310L and T1559del in tissue-nonspecific alkaline phosophatase gene are related to distinct phenotype in Japanese patients with hypophosphatasia. Eur J Pediatr. 164:277-282, 2005

Ozono K, Nakajima S, Michigami T. Vitamin D and reproductive organs. In: Feldman D, Pike JW, Glorieux FH (eds) Vitamin D, 2nd Edition. Elsevier Academic Press, Burlington, pp851-861, 2005


Ihara-Watanabe M, Uchihashi T, Miyauchi Y, Sakai N, Yamagata M, Ozono K, Michigami T. Involvement of phosphoinositide 3-kinase signaling pathway in chondrocytic differentiation of ATDC5 cells: application of a gene-trap mutagenesis. J Cell Biochem. 93:418-426, 2004

Santo Y, Hirai H, Shima M, Yamagata M, Michigami T, Nakajima S, Ozono K. Examination of megalin in renal tubular epithelium from patients with Dent disease. Pediatr Nephrol. 19:612-615, 2004


Kondou H, Mushiake S, Etani Y, Miyoshi Y, Michigami T, Ozono K. A blocking peptide for transforming growth factor-1 activation prevents hepatic fibrosis in vivo.J Hepatol. 39:742-748, 2003

Myoui A, Nishimura R, Williams PJ, Hiraga T, Tamura D, Michigami T, Mundy GR, Yoneda T. C-Src tyrosine kinase activity is associated with tumor colonization in bone and lung in an animal model of human breast cancer metastasis. Cancer Res. 63:5028-5033, 2003


Michigami T, Kageyama T, Satomura K, Shima M, Yamaoka K, Nakayama M, Ozono K. Novel mutations in the a3 subunit of vacuolar H+-adenosine triphosphatase in a Japanese patient with infantile malignant osteopetrosis. Bone. 30:436-439, 2002

Michigami T, Hiraga T, Williams PJ, Niewolna M, Nishimura R, Mundy GR, Yoneda T. The effect of the bisphosphonate ibandronate on breast cancer metastasis to visceral organs. Breast Cancer Res Treat. 75:249-258, 2002


Yamamoto T, Miyamoto K, Ozono K, Taketani Y, Katai K, Miyauchi A, Shima M, Yoshikawa H, Yoh K, Takeda E, Okada S. Hypophosphatemic rickets accompanying McCune-Albright syndrome: evidence that a humoral factor causes hypophosphatemia. J Bone Miner Metab. 19:287-295, 2001

Michigami T, Yamato H, Suzuki H, Nagai-Itagaki Y, Sato K, Ozono K. Conflicting actions of parathyroid hormone-related protein and serum calcium as regulators of 25-hydroxyvitamin D3-1-hydroxylase expression in a nude rat model of humoral hypercalcemia of malignancy. J Endocrinol. 171:249-251, 2001

Yamagata M, Kimoto A, Michigami T, Nakayama M, Ozono K. Hydroxylases involved in vitamin D metabolism are differentially expressed in murine embryonic kidney: Application of whole mount in situ hybridization. Endocrinology. 142:3223-3230, 2001

Michigami T, Ihara-Watanabe M, Yamazaki M, Ozono K. Receptor activator of NF-B ligand (RANKL) is a key molecule of osteoclast formation for bone metastasis in a newly- developed model of human neuroblastoma. Cancer Res. 61:1637-1644, 2001

Hirai H, Nakajima S, Miyauchi A, Nishimura K, Shimizu N, Shima M, Michigami T, Ozono K, Okada S. A novel activating mutation in calcium-sensing receptor gene (C129S) in a Japanese family with autosomal dominant hypocalcemia. J Hum Genet. 46:41-44, 2001


Michigami T, Shimizu N, Williams PJ, Niewolna M, Dallas SL, Mundy GR, Yoneda T. Cell-cell contact between marrow stromal cells and myeloma cells via VCAM-1 and alpha4beta1-integrin enhances production of osteoclast-stimulating activity. Blood. 96:1953-1960, 2000

Mochizuki H, Saito M, Michigami T, Ohashi H, Koda N, Yamaguchi S, Ozono K. Severe hypercalcemia and respiratory insufficiency associated with infantile hypophosphatasia caused by two novel mutations of the TNSALP gene. Eur J Pediatr. 159:375-379, 2000

Muller HL, Yamazaki M, Michigami T, Kageyama T, Schonau E, Schneider P, Ozono K. Asp361Val mutant of alkaline phosphatase found in patients with dominantly inherited hypophosphatasia inhibits the activity of the wild-type enzyme. J Clin Endocrinol Metab. 85:743-747, 2000

Yanagihara I, Yamagata M, Sakai N, Shukunami C, Kurahashi H, Yamazaki M, Michigami T, Hiraki Y, Ozono K. Genomic organization of the human chondromodulin-1 gene containing a promoter region which confers the expression of reporter gene in chondrogenic ATDC5 cells. J Bone Miner Res. 15:421-429, 2000


Michigami T, Suga A, Yamazaki M, Shimizu C, Cai G, Okada S, Ozono K. Identification of amino acid sequence in the hinge region of human vitamin D receptor which transfers a cytosolic protein to the nucleus. J Biol Chem. 274: 33531-33538, 1999

Ozono K, Saito M, Miura D, Michigami T, Nakajima S, Ishizuka S. Analysis of the molecular mechanism for the antagonistic action of a novel 1,25-dihydroxyvitamin D3 analogue toward vitamin D receptor function. J Biol Chem. 274:32376-32381, 1999

Yoneda T, Michigami T, Yi B, Williams PJ, Niewolna M, Hiraga T. Use of bisphosphonates for the treatment of bone metastasis in experimental animal models. Cancer Treat Rev. 25:293-299, 1999


Michigami T, Nomizu M, Yamada Y, Dunstan C, Williams PJ, Mundy GR, Yoneda T. Growth and dissemination of a newly-established murine B-cell lymphoma cell line is inhibited by multimeric YIGSR peptide. Clin Exp Metastasis. 16:645-654, 1998

Cai G, Michigami T, Yamamoto T, Yasui N, Satomura K, Yamagata M, Shima M, Nakajima S, Mushiake S, Okada S, Ozono K. Analysis of localization of mutated tissue-nonspecific alkaline phosphatase proteins associated with neonatal hypophosphatasia using green fluorescent protein chimeras. J Clin Endocrinol Metab. 83:3936-3942, 1998


Ozono K, Yamagata M, Michigami T, Nakajima S, Sakai N, Cai G, Satomura K, Yasui N, Okada S, Nakayama M. Identification of novel mutations (Phe310Leu and Gly439Arg) in a neonatal case of hypophosphatasia. J Clin Endocrinol Metab. 81:4458-4461, 1996

Michigami T, Yamato H, Mushiake S, Nakayama M, Yoneda A, Satomura K, Imura K, Ozono K. Hypercalcemia associated with infantile fibrosarcoma producing parathyroid hormone-related protein. J Clin Endocrinol Metab. 81:1090-1095, 1996

Yamamoto T, Ozono K, Kasayama S, Yoh K, Hiroshima K, Takagi M, Matsumoto S, Michigami T, Yamamoto K, Kishimoto T, Okada S. Increased IL-6 production by cells isolated from the fibrous bone dysplasia tissues in patients with McCune-Albright syndrome. J Clin Invest. 98:30-35, 1996


Toshimi Michigami, M.D., Ph.D.

Department of Bone and Mineral Research

Research Institute

Osaka Medical Center for Maternal and Child Health 840 Murodo-cho, Izumi, Osaka 594-1101, Japan

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