Hisashi Shinoda

Anchorage and retentive effects of a bisphosphonate (AHBuBP) on tooth movements in rats.

The purpose of this study was to examine the effect of 4-amino-1-hydroxybutylidene-1,1-bisphosphonate (AHBuBP), a potent blocker of bone resorption, on orthodontic tooth movements in rats. In the first experiment, the right and left upper first molars were moved buccally for 3 weeks with a uniform standardized expansion spring under systemic administration of AHBuBP every other day. The total tooth movement during the 3-week experimental period was 40% of that in the control at a dose of 0.5 mg P/kg. In the second experiment, the right and left upper first molars were first moved buccally for 3 weeks without AHBuBP. The spring was then removed and administration of AHBuBP was initiated. The total relapse movement during the 3-week experimental period was 50% of that in the control at a dose of 0.5 mg P/kg. Results of the first and second experiments were both dose dependent. Histologic examination showed that in the experimental animals fewer osteoclasts appeared on the alveolar bone surface, and both bone resorption and root resorption were inhibited. Inhibition of tooth movement was also observed when AHBuBP was applied topically. These results suggest that AHBuBP could be useful in enhancing anchorage or retaining teeth in orthodontic treatment.

Effects of Topical Administration of a Bisphosphonate (Risedronate) on Orthodontic Tooth Movements in Rats

In orthodontics, undesirable movement of anchor teeth during tooth movement and relapse of moved teeth after treatment are the main causes of unsuccessful results. If these tooth movements could be prevented with pharmacological agents, a less complex orthodontic force system and less extensive retention would be required. The purpose of this study was to examine the effect of topical administration of a bisphosphonate (risedronate), a potent blocker of bone resorption, on orthodontic tooth movements in rats. In the first experiment, both the right and left upper first molars were moved buccally with a standardized expansion spring under administration of risedronate. Risedronate solution was injected into the sub-periosteum area adjacent to the left upper first molar. The right first molar served as a control with an injection of 0.9% NaCl solution. The topical administration of risedronate caused a significant and dose-dependent reduction of tooth movement after the orthodontic force was applied. In the second experiment, the right and left upper molars were first moved buccally for three weeks. The spring was then removed, and administration of risedronate was begun. The topical administration of risedronate inhibited relapse of the tooth in a dose-dependent manner. The administration of risedronate did not affect either overall growth of the animals or longitudinal growth of tibiae. These results suggest that topical application of risedronate may be helpful in anchoring and retaining teeth under orthodontic treatment.

Inhibitory Effect of the Topical Administration of a Bisphosphonate (Risedronate) on Root Resorption Incident to Orthodontic Tooth Movement in Rats

Root resorption associated with tooth movement is an unsolved problem in orthodontics. If such root resorption could be prevented, it would be an important contribution toward reducing risk factors in orthodontic treatment. The purpose of this study was to examine the effects of the topical administration of a bisphosphonate, risedronate, which is known to be a potent blocker of bone resorption, on root resorption during tooth movement and on the repair of the resorbed root surface after tooth movement in rats. In the first experiment, both the right and left upper first molars were moved buccally with a standardized expansion spring under administration of risedronate. After day 7, extensive root resorption had occurred on the control side, and the area of root resorption reached a maximum on day 14. The topical administration of risedronate caused a significant and dose-dependent inhibition of root resorption after the orthodontic force was applied. In the second experiment, the right and left upper molars were first moved buccally for 3 weeks. Risedronate treatment began on the day the spring was removed. After the force was withdrawn, the resorbed root surfaces on both the control and risedronate-treated sides were gradually restored by apposition of repair cementum (cementoid). The topical administration of risedronate did not appear to inhibit the repair process of root resorption. These results suggest that the topical administration of risedronate may be useful in preventing root resorption of teeth during orthodontic treatment.

Aminoalkylbisphosphonates, potent inhibitors of bone resorption, induce a prolonged stimulation of histamine synthesis and increase macrophages, granulocytes, and osteoclasts in vivo

SummaryAminoalkyl derivatives of bisphosphonates are potent inhibitors of bone resorption. A single I.P. injection of 4-amino-1-hydroxybutylidene-1,1-bis-phosphonate (AHBuBP) induced a prolonged enhancement of histidine decarboxylase (HDC) activity in the bone marrow, spleen, lung, and liver of mice and resulted in an increase in histamine. The induction of HDC by the agent was dose dependent (16–80 μmol/kg) and peaked 3–4 days after its injection (40 μmol/kg). Repeated S.C. injections of smaller doses of AHBuBP (0.32 or 1.6 μmol/kg/day) for 4 days also enhanced HDC activity. However, the minimum dose capable of inhibiting bone resorption (0.064 μmol/kg/day) was lower than that inducing HDC. Unexpectedly, AHBuBP, at the doses inducing HDC, increased macrophages, granulocytes, and even osteoclasts. The size of osteoclasts was also enlarged by the agent. Another aminobisphosphonate, 3-amino-1-hydroxypropylidene-1,1-bisphosphonate, but none of nonamino derivatives, also exhibited essentially the same effects as those of AHBuBP. These results indicate that in spite of increase in osteoclasts and their enlargement, bone resorption is still inhibited by amino bisphosphonates. As granulocyte and granulocyte-macrophage colony-stimulating factors and interleukin-3 induce HDC in hematopoietic organs, and histamine has a hematopoietic activity, the HDC induction by aminobisphosphonates may be relevant to the proliferation of progenitor cells of macrophages, granulocytes, and osteoclasts.

Activin release from bone coupled to bone resorption in organ culture of neonatal mouse calvaria.

Activin, a member of the transforming growth factor-beta (TGF-beta) superfamily, is present in the bone matrix and assumed to be involved in the regulation of bone formation. In the present study, we investigated whether the release of activin from bone is coupled with bone resorption. Neonatal mouse calvaria were cultured in the presence of various stimulators of bone resorption (parathyroid hormone [PTH], interleukin-1beta, prostaglandin E2) for up to 72 h, and the activin activity in the medium was measured using a specific bioassay for activin. Activin activity was accumulated in proportion to the time- and dose-dependent increase in calcium release from bone into the medium (bone resorption). An inhibition of PTH-dependent bone resorption by a bisphosphonate, disodium dichlormethane-1,1-bisphosphonic acid (Cl2MBP), completely blocked release of activin activity from bone into the medium. In primary culture of calvarial cells, however, neither PTH nor Cl2MBP affected activin production. These findings indicate that release of activin activity from bone tissue is strongly coupled to bone resorption. Because activin possesses osteogenic activities, activin released locally from bone might be involved in the regulation of bone formation in the physiological process of bone remodeling, as has been suggested for TGF-beta.

Distribution of Artificial Radionuclides in Abandoned Cattle in the Evacuation Zone of the Fukushima Daiichi Nuclear Power Plant

The Fukushima Daiichi Nuclear Power Plant (FNPP) accident released large amounts of radioactive substances into the environment. In order to provide basic information for biokinetics of radionuclides and for dose assessment of internal exposure brought by the FNPP accident, we determined the activity concentration of radionuclides in the organs of 79 cattle within a 20-km radius around the FNPP. In all the specimens examined, deposition of Cesium-134 (134Cs, half-life: 2.065 y) and 137Cs (30.07 y) was observed. Furthermore, organ-specific deposition of radionuclides with relatively short half-lives was detected, such as silver-110m (110mAg, 249.8 d) in the liver and tellurium-129m (129mTe, 33.6 d) in the kidney. Regression analysis showed a linear correlation between the radiocesium activity concentration in whole peripheral blood (PB) and that in each organ. The resulting slopes were organ dependent with the maximum value of 21.3 being obtained for skeletal muscles (R2 = 0.83, standard error (SE) = 0.76). Thus, the activity concentration of 134 Cs and 137Cs in an organ can be estimated from that in PB. The level of radioactive cesium in the organs of fetus and infants were 1.19-fold (R2 = 0.62, SE = 0.12), and 1.51-fold (R2 = 0.70, SE = 0.09) higher than that of the corresponding maternal organ, respectively. Furthermore, radiocesium activity concentration in organs was found to be dependent on the feeding conditions and the geographic location of the cattle. This study is the first to reveal the detailed systemic distribution of radionuclides in cattle attributed to the FNPP accident.

Effects of bisphosphonates on alkaline phosphatase activity, mineralization, and prostaglandin E2 synthesis in the clonal osteoblast- like cell line MC3T3-E1

The effects of 3 bisphosphonates, AHBuBP, AHPrBP, and Cl2MBP on cell growth, alkaline phosphatase (ALP) activity, mineralization, and prostaglandin E2 (PGE2) synthesis in the clonal osteoblast-like cell line MC3T3-E1 were studied. These bisphosphonates had essentially similar effects on growth and the osteoblastic functions of the cells, i.e., they had no inhibitory effects on cell growth except at higher concentrations, they increased ALP activity, and inhibited PGE2 production. In the presence of AHBuBP, ALP activity was higher than that in the control after day 6 of culture. Lower concentrations of AHBuBP slightly facilitated mineralization by the cells. It is probable that bisphosphonates enhance the functions of osteoblasts in certain concentration and that the inhibition of endogenous PGE2 production may be involved in the mechanism of action of bisphosphonates.

Effects of radioactive caesium on bull testes after the Fukushima nuclear plant accident

We aimed to investigate the effect of chronic radiation exposure associated with the Fukushima Daiichi Nuclear Plant accident on the testis from 2 bulls. Estimated dose of internal exposure in one bull was 0.7–1.2 mGy (134Cs) and 0.4–0.6 mGy (137Cs) and external exposure was 2.0 mGy (134Cs) and 0.8 mGy (137Cs) (196 days). Internal dose in the other was 3.2–6.1 mGy (134Cs) and 1.8–3.4 mGy (137Cs) and external dose was 1.3 mGy (134Cs) and 0.6 mGy (137Cs) (315 days). Sperm morphology and spermatogenesis were within normal ranges. 134, 137Cs radioactivity was detected but Cs was not detectable in the testis by electron probe microanalysis. Thus, adverse radiation-induced effects were not observed in bull testes following chronic exposure to the above levels of radiation for up to 10 months. Since we could analyse a limited number of testes, further investigation on the effects of ionizing radiation on spermatogenesis should be extended to more animals.

Platelet‐leukocyte interaction in adhesion to endothelial cells induced by platelet‐activating factor in vitro

1 Platelet‐activating factor (PAF, 10 nm) did not induce platelet adhesion to endothelial cells cultured in monolayer but it induced their adhesion to protein‐coated plastic. However, PAF induced a marked platelet adhesion to endothelial cells when polymorphonuclear leukocytes (PMNs) were present. Lyso‐PAF had no effect. 2 Phase‐contrast microscopic examination showed that single platelets rather than their aggregates adhered to the endothelial cell surface around aggregating and adhering PMNs. 3 Significant platelet adhesion was induced by PAF at concentrations higher than 0.01 nm with the maximal response at 10 nm. Platelet adhesion occurred within minutes after PAF addition, reaching a maximum approximately after 30 min. Platelet adhesion also occurred significantly at a PMN: platelet ratio of 1:800, and linearly up to 1:50. 4 The PAF‐induced platelet adhesion was suppressed by three structurally unrelated PAF antagonists, WEB 2086, ONO 6240 and BN 52021, in a concentration‐dependent manner. 5 PAF also increased PMN adhesion to endothelial cell monolayers, which was further augmented by the presence of platelets. 6 The present study demonstrates that PAF induces platelet adhesion to endothelial cells in vitro when PMNs are present and that there is a close interaction between platelets and PMNs in their adhesion to endothelial cells. The present study further suggests that PMNs could play a central role in platelet adhesion to vascular endothlium in certain pathological conditions.

Clodronate Inhibits PGE2 Production in Compressed Periodontal Ligament Cells

Periodontal ligament (PDL) cells play an essential role in orthodontic tooth movement. We recently reported that clodronate, a non-N-containing bisphosphonate, strongly inhibited tooth movement in rats, and thus could be a useful adjunct for orthodontic treatment. However, it is not clear how clodronate affects the responses of PDL cells to orthodontic force. In this study, we hypothesized that clodronate prevents the mechanical stress-induced production of prostaglandin E2 (PGE2), interleukin-1β (IL-1β), and nitric oxide (NO) in human PDL cells. A compressive stimulus caused a striking increase in PGE2 production, while the responses of IL-1β and NO were less marked. Clodronate concentration-dependently inhibited the stress-induced production of PGE2. Clodronate also strongly inhibited stress-induced gene expression for COX-2 and RANKL. These results suggest that the inhibitory effects of clodronate on tooth movement and osteoclasts may be due, at least in part, to the inhibition of COX-2-dependent PGE2 production and RANKL expression in PDL cells.