Biomedical subjects

Yasuhiro Takeuchi

Publications and source records attributed to Yasuhiro Takeuchi.

25 records · Page 2Linked to original sources

PubMed2002

Increased circulatory level of biologically active full-length FGF-23 in patients with hypophosphatemic rickets/osteomalacia.

Hypophosphatemic rickets/osteomalacia with inappropriately low serum 1,25-dihidroxyvitamin D level is commonly observed in X-linked hypophosphatemic rickets/osteomalacia, autosomal dominant hypophosphatemic rickets/osteomalacia and tumor-induced osteomalacia. Although the involvement of a newly identified factor, FGF-23, in the pathogenesis of ADHR and TIO has been suggested, clinical evidence indicating the role of FGF-23 has been lacking. We have previously shown that FGF-23 is cleaved between Arg(179) and Ser(180), and this processing abolished biological activity of FGF-23 to induce hypophosphatemia. Therefore, sandwich ELISA for biologically active intact human FGF-23 was developed using two kinds of monoclonal antibodies that requires the simultaneous presence of both the N-terminal and C-terminal portion of FGF-23. The serum levels of FGF-23 in healthy adults were measurable and ranged from 8.2 to 54.3 ng/L. In contrast, those in a patient with TIO were over 200 ng/L. After the resection of the responsible tumor, the elevated FGF-23 level returned to normal level within 1 h. The increase of serum concentrations of 1,25-dihidroxyvitamin D and phosphate, and the decrease of serum 24,25-dihydroxyvitamin D followed the change of FGF-23. In addition, the elevated serum FGF-23 levels were demonstrated in most patients with XLH. It is likely that increased serum levels of FGF-23 contributes to the development of hypophosphatemia not only in TIO but also in XLH.

Adult↗

PubMed2002

Stimulation of Smad1 transcriptional activity by Ras-extracellular signal-regulated kinase pathway: a possible mechanism for collagen-dependent osteoblastic differentiation.

Signals from bone morphogenetic protein receptors (BMPRs) and cell adhesion to type I collagen are both important for osteoblastic differentiation and functions. BMP signals are mediated mostly by Smad and collagen signals are transduced by integrins to activate focal adhesion kinase (FAK) and its downstream molecules. This study was undertaken to clarify how extracellular matrix collagen signals converge with BMP actions. We show that integrin activation by collagen was involved in BMP signals because disruption of either collagen synthesis or collagen-alpha2beta1-integrin binding inhibited the stimulatory effect of BMP-2 on osteoblastic MC3T3-E1 cells. Downstream signals of collagen-integrin might be FAK-Ras-extracellular signal-regulated kinase (ERK) in osteoblastic cells. We further show that Ras-ERK signals enhanced the transcriptional activity of Smad1 in response to BMP in these cells transiently transfected with expression plasmids for a constitutively active mutant RasV12, a dominant negative mutant RasN17, and an ERK phosphatase CL100. Ras-ERK signals did not augment the transcriptional activity of Smad3 in response to transforming growth factor beta (TGF-beta) receptor activation but that of Smad1 in response to BMPR activation as examined in COS-1 cells. These observations suggest that the Ras-ERK pathway downstream of integrin-FAK is involved in Smad1 signals activated by BMP and provide a possible mechanism for cooperation between intracellular signals activated by integrin and BMPRs in osteoblastic cells.

Activin Receptors, Type I↗

PubMed2002

Parathyroid hormone-related protein induced coupled increases in bone formation and resorption markers for 7 years in a patient with malignant islet cell tumors.

Parathyroid hormone-related protein (PTHrP) and PTH share the common PTH/PTHrP receptor. Although an elevated level of circulating PTHrP in patients with malignancies causes hypercalcemia as does PTH, chronic and systemic effects of PTHrP on bone metabolism in humans are not well understood because tumor-burden patients showing hypercalcemia usually have a poor prognosis. We investigated bone and calcium metabolism in a patient with malignant islet cell tumors showing hypercalcemia due to the elevated plasma PTHrP level for 7 years. Hypercalcemia and hypercalciuria continued throughout the clinical course in spite of frequent infusions of bisphosphonates. Bone resorption markers and a bone formation marker were consistently elevated as seen in primary hyperparathyroidism, a disease caused by an autonomous hypersecretion of PTH. Based on biochemical measurements including bone markers and serum 1,25-dihydroxyvitamin D, the clinical features of this case essentially are the same as those of primary hyperparathyroidism except for the elevated level of plasma PTHrP with suppressed intact PTH level. Therefore, it is suggested that chronic and systemic effects of PTHrP on bone as well as calcium metabolism are indistinguishable from those of PTH in human.

Adult↗

PubMed2002

Clonal endothelial cells produce humoral factors that inhibit osteoclast-like cell formation in vitro.

Angiogenesis and bone remodeling are closely associated, and vascular endothelial cells may have potential roles for osteoclastic bone resorption. We examined whether clonal endothelial cells established from bone, aorta and brain of Balb/c mice influenced osteoclast-like cell formation in vitro. As low as 1% conditioned media of those endothelial cells inhibited osteoclast-like cell formation in bone marrow cultures induced by 1,25-dihydroxyvitamin D3, and did so in spleen cell cultures in the presence of soluble receptor activator of nuclear factor-kappaB ligand (RANKL), M-CSF and prostaglandin E2. The level of osteoprotegerin (OPG), a decoy receptor for RANKL, secreted by endothelial cells was not high enough to inhibit osteoclastogenesis. These observations suggest that endothelial cells derived from various tissues secrete factor(s) that inhibits precursors to differentiate into osteoclasts even in the presence of optimal stimulators for osteoclastogenesis. Hence, endothelial cells in bone may inhibit recruitment of fresh osteoclasts, and those in tissues other than bone may be involved in prohibiting ectopic osteoclastogenesis.

Animals↗

PubMed2002

[Stevens-Johnson syndrome accompanied by acute hepatitis in workers exposed to trichloroethylene or tetrachloroethylene].

Since the late 1980s, there has been an increasing tendency in the number of case reports on Stevens-Johnson syndrome accompanied by acute hepatitis in workers exposed to trichloroethylene from Asian countries. Recently, mass outbreaks of it have been disclosed in the Philippines and China. Besides trichloroethylene, although the number is small, a similar health disorder has also occurred in workers using tetrachloroethylene. Since the above-mentioned facts are not yet well recognized in the occupational health community, this review is aimed at making clear (1) the clinical features of the health disorder, (2) details of patients' jobs, working environments, and exposure to hazardous chemicals, and (3) the relationship between exposure to trichloroethylene or tetrachloroethylene and the health disorder. Based on a critical review of articles, the following were pointed out. First, it is important to carefully observe the health status of workers exposed to trichloroethylene or tetrachloroethylene and to take countermeasures to reduce exposure. Secondly, circumstantial evidence suggests a cause-effect relationship between the two chemicals and the health disorder; but at the present time it is impossible to rule out the participation of unelucidated factors promoting the occurrence of the health disorder or the existence of a hidden genuine causative substance. Therefore further investigation to trace such a case is needed. Thirdly, the mechanism of the health disorder and the reason why there seems to be a large inter-individual difference in sensitivity to the causative agent should be clarified.

Acute Disease↗

PubMed2002

Involvement of caspase 3 mediated apoptosis in hematopoietic cytotoxicity of metabolites of ethylene glycol monomethyl ether.

The hematopoietic toxicity of ethylene glycol monomethyl ether (EGME) and its metabolites, methoxy acetaldehyde (MALD) and methoxyacetic acid (MAA), was analyzed using human bone marrow cells from a lymphoma patient without bone marrow involvement and a human leukemia cell line, HL60. After 24-hour incubation, the concentrations of 50 percent inhibition (IC50) of human hematopoietic progenitor cells with MALD or MAA were 3 mM and 3.9 mM, respectively, and EGME (10 mM or more) did not show any cytotoxicity. IC50 (after 48-hour exposure) of MALD and MAA on HL60 cells were 2.45 mM and 5.6 mM, respectively, suggesting that both hematopoietic progenitor cells and HL60 have a similar sensitivity. DNA ladder formation, a characteristics of apoptosis, was observed in MALD- or MAA-treated HL60 cells, but not in EGME-treated samples. Caspase-3 enzyme activity, the effector of the apoptotic process, was greatly enhanced with MALD treatment. The inhibitor of caspase-3 repressed cell death induced with MALD as well as MAA.

Acetaldehyde↗

PubMedDate not supplied

Xenotransplantation and pig endogenous retroviruses.

Xenotransplantation, in particular transplantation of pig cells, tissues and organs into human patients, may alleviate the current shortage of suitable allografts available for human transplantation. This overview addresses the physiological, immunological and virological factors considered with regard to xenotransplantation. Among the issues reviewed are the merits of using pigs as xenograft source species, the compatibility of pig and human organ physiology and the immunological hindrances with regard to the various types of rejection and attempts at abrogating rejection. Advances in the prevention of pig organ rejection by creating genetically modified pigs that are more suited to the human microenvironment are also discussed. Finally, with regard to virology, possible zoonotic infections emanating from pigs are reviewed, with special emphasis on the pig endogenous retrovirus (PERV). An in depth account of PERV studies, comprising their discovery as well as recent knowledge of the virus, is given. To date, all retrospective studies on patients with pig xenografts have shown no evidence of PERV transmission, however, many factors make us interpret these results with caution. Although the lack of PERV infection in xenograft recipients up to now is encouraging, more basic research and controlled animal studies that mimic the pig to human xenotransplantation setting more closely are required for safety assessment.

Animals↗