We demonstrated previously that a single injection of recombinant human macrophage colony-stimulating factor (rhM-CSF) is sufficient for osteoclast recruitment and survival in osteopetrotic (op/op) mice with a deficiency in osteoclasts resulting from a mutation in M-CSF gene. In this study, we show that a single injection of recombinant human vascular endothelial growth factor (rhVEGF) can similarly induce osteoclast recruitment in op/op mice. Osteoclasts predominantly expressed VEGF receptor 1 (VEGFR-1), and activity of recombinant human placenta growth factor 1 on osteoclast recruitment was comparable to that of rhVEGF, showing that the VEGF signal is mediated through VEGFR-1. The rhM-CSF–induced osteoclasts died after injections of VEGFR-1/Fc chimeric protein, and its effect was abrogated by concomitant injections of rhM-CSF. Osteoclasts supported by rhM-CSF or endogenous VEGF showed no significant difference in the bone-resorbing activity. op/op mice undergo an age-related resolution of osteopetrosis accompanied by an increase in osteoclast number. Most of the osteoclasts disappeared after injections of anti-VEGF antibody, demonstrating that endogenously produced VEGF is responsible for the appearance of osteoclasts in the mutant mice. In addition, rhVEGF replaced rhM-CSF in the support of in vitro osteoclast differentiation. These results demonstrate that M-CSF and VEGF have overlapping functions in the support of osteoclastic bone resorption.

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The purpose of this study was to clarify the prevalence and degree of root resorption induced by orthodontic treatment in association with treatment factors. The files of 243 patients (72 males and 171 females) aged 9-51 years were randomly selected from subjects treated with multi-bracket appliances. The severity of root resorption was classified into five categories on radiographs taken before and after treatment. The subjects were divided into extraction (n = 113 patients, 2805 teeth) and non-extraction (n = 130 patients, 3616 teeth) groups and surgical (n = 56 patients, 1503 teeth) and non-surgical treatment (n = 187 patients, 4918 teeth) groups. These subjects were also divided into two or three groups based on the duration of multiloop edgewise archwire (MEAW) treatment, elastic use, and total treatment time: 0 month (T1; n = 184 patients, 4831 teeth), range 1-6 months (T2; n = 37 patients, 994 teeth), more than 6 months (T3; n = 22 patients, 596 teeth); range 0-6 months (n = 114 patients, 3016 teeth) more than 6 months (n = 129 patients, 3405 teeth); range 1-30 months (n = 148 patients, 3913 teeth) and more than 30 months (n = 95 patients, 2508 teeth). The prevalence of overall and severe root resorption evaluated by the number of subjects and teeth was compared with a chi-square test. A Student's t-test for unpaired data was used to determine any statistically significant differences. The prevalence of severe root resorption based on the number of teeth was significantly higher in the group with extractions (P < 0.01). Longer use of a MEAW appliance and elastics also produced a significantly higher prevalence of root resorption (P < 0.05). On the other hand, the prevalence of severe root resorption was not significantly different between the subjects treated with or without surgery, but there was a significant increase when treatment time was prolonged (P < 0.05). A significant difference was found in the amount of root movement of the upper central incisors and the distance from their root apices to the cortical bone surface (P < 0.05). These are regarded as essential factors in the onset of root resorption. These results indicate that orthodontic treatment with extractions, long-term use of a MEAW appliance and elastics, treatment time, and distance of tooth movement are risk factors for severe root resorption.

Vascular endothelial growth factor (VEGF) has an ability to induce functional osteoclasts as well as neovascularization. We recently reported that the number of osteoclasts was enhanced by the injection of recombinant human VEGF (rhVEGF) with the application of mechanical force for experimental tooth movement. In this study, the expression of VEGF was detected in osteoblasts on the tension side of the alveolar bone. Moreover, the rate of tooth movement was significantly increased in the rhVEGF injection groups compared with the controls. These results suggested that VEGF, highly expressed by mechanical stimuli, enhances the number of osteoclasts as a paracrine factor, and that the amount of tooth movement is accelerated by both endogenous VEGF and injected rhVEGF.

It is well-known that sex hormones influence bone metabolism. However, it remains unclear as to how sex hormones affect bone growth in newborn mice. In this study, we performed orchiectomy (ORX) and ovariectomy (OVX) on newborn mice, and examined the effects on craniofacial growth morphometrically. ORX and OVX were performed on five-day-old C57BL/6J mice. Four weeks after surgery, lateral cephalograms were taken of all of the mice, with the use of a rat and mouse cephalometer. Cephalometric analysis of the craniofacial skeleton was performed by means of a personal computer. Inhibition of craniofacial growth was found in the experimental groups but not in the sham-operated groups. In the nasomaxillary bone and mandible, the amount of growth was significantly reduced. These results suggest that craniofacial growth is inhibited by sex hormone disturbances not only in puberty but also immediately after birth.

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It has been reported that reduction of masticatory afferent stimulation might influence learning and memory function. In order to clarify the influences of reduced masticatory sensory input on spatial memory/learning ability and neuropathological changes, we conducted the Morris water maze experiment and investigated the number of hippocampal neurons in association with the differences in masticatory afferent stimuli from hard-and soft-diet feeding in mice. The water maze experiment showed no significant difference in learning ability between 180-day-old solid-and powderdiet groups. Meanwhile, the ability was significantly reduced in the 360-day-old powder-diet group as compared with the age-matched solid-diet group. The total number of pyramidal cells in the hippocampal CA1 and CA3 regions was significantly smaller in 360-day-old powder-diet group than in the remaining groups. These results demonstrate that reduction of masticatory afferent stimuli due to long-term soft-diet feeding may induce neuron loss in the hippocampus and reduced memory/learning ability.Alzheimer's disease (AD) is a progressive neurodegenerative disorder, which was first reported by Alzheimer in 1907 (1, 18). It is, in general, divided into early and late-onset types, but both have similar clinical and pathological features. It has long been suggested that there is a certain relationship between loss of teeth and dementia. Kondo et al. (6) reported that tooth loss was one of the risk factors of AD. Shigetomi et al. (17) reported that the risk of AD onset increased significantly in a group with lessnumber teeth than in the age-matched control with more-number teeth. Animal experiments revealed that tooth loss or long-term soft-diet feeding caused a decrease of learning and memory ability. Yamamoto and Hirayama showed that the SAMR1 and SAMP8 mice fed on a solid diet were superior in an eight-arm radial maze to the powder-diet group (21). It was also reported that the aged SAMP8 mice, after the molar extraction, showed a decrease in both learning ability and neuron density in the hippocampal CA1 region compared with the controls (14). Furthermore, it is suggested that afferent sensory input is highly dependent on masticatory function or hardness of the diet (13). Ishizuka (5) demonstrated that the action potential of the masseter muscle in rats was significantly lower in the powder-diet group than in the solid-diet group.It is reasonably assumed from these findings that tooth loss and the relevant reduction of masticatory afferent stimuli may influence the structure and function of the central nervous system (CNS). However, little information is available for the relation-

recombinant human vascular endothelial growth factor (rhVEGF), macrophage colony-stimulating factor (M-CSF), osteopetrotic mice (op/op mice),fms-like tyrosine kinase (Flt-1), periodontal ligament (PDL), phosphate-buffered saline (PBS), tartrate-resistant acid phosphatase (TRAP), and analysis of variance (ANOVA).