The homeostasis of the plasma phosphate level is essential for many biological processes including skeletal mineralization. The reabsorption of phosphate in the kidney is a major determinant of the plasma levels of phosphate. Phosphatonin is a hormone-like factor that specifically inhibits phosphate uptake in renal proximal epithelial cells. Recent studies on tumor-induced osteomalacia suggested that phosphatonin was potentially identical to fibroblast growth factor (FGF)-23. However, as purified recombinant FGF-23 could not inhibit phosphate uptake in renal proximal epithelial cells, the mechanism of action of FGF-23 remains to be elucidated. Therefore, we examined the mechanism of action of FGF-23 in cultured renal proximal epithelial cells, opossum kidney cells. FGF-23 was found to require heparinlike molecules for its inhibitory activity on phosphate uptake. FGF-23 binds to the FGF receptor 3c, which is mainly expressed in opossum kidney cells, with high affinity. An inhibitor for tyrosine kinases of the FGF receptor, SU 5402, blocked the activity of FGF-23. FGF-23 activated the mitogen-activated protein kinase (MAPK) pathway, which is the major intracellular signaling pathway of FGF. Inhibitors of the MAPK pathway, PD98059 and SB203580, also blocked the activity of FGF-23.ThepresentfindingshaverevealedanovelMAPKdependent mechanism of the regulation of phosphate uptake by FGF signaling.Phosphate is a nutrient essential for many biological processes including skeletal mineralization and energy metabolism (1). The homeostasis of the plasma phosphate level is essential for these processes. The reabsorption of phosphate in the kidney is a major determinant of the plasma phosphate level. Reabsorption is largely regulated by the type II sodium-dependent phosphate (Na/P i ) cotransporter that is expressed in renal proximal epithelial cells (1). The activity of the type-II Na/P i cotransporter is regulated by hormones, such as parathyroid hormone (PTH) 1 and 1,25-dihydroxyvitamin D (1,25(OH) 2 D), which have opposite effects. PTH and 1,25(OH) 2 D decrease and increase the reabsorption of phosphate in renal proximal tubules, respectively (1). Tumor-induced osteomalacia is a renal phosphate-wasting disorder resulting in low serum phosphorus concentration and osteomalacia. Removal of the tumors responsible for tumorinduced osteomalacia normalizes phosphate metabolism. The responsible tumors secrete a heat-sensitive molecule of ϳ25 kDa designated as "phosphatonin" that specifically inhibits sodium-dependent phosphate transport in cultured renal proximal epithelial cells. Recent studies on tumor-induced osteomalacia revealed that phosphatonin was potentially identical to fibroblast growth factor (FGF)-23, which is a new member of the FGF family (2, 3, 5). Autosomal dominant hypophosphataemic rickets is also a renal phosphate-wasting disorder resulting in low serum phosphorus concentration, rickets, and osteomalacia. The ADHR gene was also potentially identified to be FGF-23 with missense mutations (4). However, as puri...

The findings indicated that the genetic polymorphisms of CYP2C isozymes play an important role in the pharmacokinetic variability of phenytoin and that the mutation in CYP2C9 proteins (Ile359-->Leu) is a determinant of impaired metabolism of the drug among Japanese persons.

We investigated the effects of low-intensity pulsed ultrasound on distraction osteogenesis in a rabbit model.Callotasis of the right tibia was performed in 70 male Japanese white rabbits using mini-external fixators. In the first part of the study in 64 animals using normal distraction (waiting period seven days; distraction rate 0.5 mm/12 hours; distraction period ten days), we evaluated the distraction site by radiography, measurement of the bone mineral density (BMD), mechanical testing, and histology. In the second part in six rabbits using fast distraction (waiting period 0 days; distraction rate 1.5 mm/12 hours; distraction period seven days) the site was evaluated radiologically. Half of the animals (35) had received ultrasound to their right leg (30mW/cm 2 ) for 20 minutes daily after ceasing distraction (ultrasound group), while rigid fixation only was maintained in the other half (control group). With normal distraction, the hard callus area, as shown by radiography, the BMD, and the findings on mechanical testing, were significantly greater in those receiving ultrasound than in the control group. Histological analysis showed no tissue damage attributable to exposure to ultrasound. With fast distraction, immature bone regeneration was observed radiologically in the control group, while bone maturation was achieved in the ultrasound group.We conclude that ultrasound can accelerate bone maturation in distraction osteogenesis in rabbits, even in states of poor callotasis.

Fibroblast growth factor (FGF) has been reported to increase the volume of callus in a fracture model of rats. There are, however, no reports of successful repair of segmental bony defects by application of an FGF solution. In this study, the effects of basic FGF on the repair of segmental bony defects in the rabbit femur were examined. Minipellet, a new drug delivery system using atelocollagen, was employed to ensure effective delivery of FGF. Segmental bony defects (10 mm in length) were created in the right femurs of 19 rabbits. In pilot studies, no defects of this size healed spontaneously within 6 weeks. Bones were stabilized with miniexternal fixators. Minipellets containing basic FGF were implanted between fragments so as to bridge the two fragments. The healing processes were monitored radiographically and studied histologically. In rabbits in which FGF was added to the defect site at doses of 1.4 microgram or higher, approximately 90% of the defects were filled with new bone and cartilage within 6 weeks after minipellet implantation. In rabbits receiving placebo minipellets, however, approximately 15% of the defects were filled by callus within 6 weeks. Furthermore, this callus did not change into mature bone. An injection of 2 microgram of FGF solution to bony defects had no effect on the repair of segmental bony defects. These findings suggest that FGF plays a role in the production of adequate volumes of callus particularly in the initial stages of fracture healing and that sustained local release enables FGF to be effective at a low dose. In summary, large segmental bony defects healed after insertion of low-dose FGF minipellets. An adequate dose of FGF and an appropriate delivery system are required for successful healing of large bony defects. These findings imply the potential value of FGF minipellets in clinical practice.

A surgical case of pulmonary metastases of polymorphous low-grade adenocarcinoma (PLGA) originating from the minor salivary gland in the soft palate in a 62-year-old woman is reported. PLGA has been to be a locally invasive carcinoma without distant metastases; thus our case is the first reported case with histologically-proven distant metastases to the lung. We emphasise that attention should be paid to distant metastases especially to the lung even in case of PLGA.