About half of human conceptions are estimated not to be implanted in the uterus, resulting in unrecognizable spontaneous abortions, and about 5% of human births have a recognizable malformation. In order to find clues to the mechanisms of malformation and abortion, we compared the incidences of radiation-induced malformations and abortions in p53 null (p53-/-) and wild-type (p53+/+) mice. After X-irradiation with 2 Gy on day 9.5 of gestation, p53-/- mice showed a 70% incidence of anomalies and a 7% incidence of deaths, whereas p53+/+ mice had a 20% incidence of anomalies and a 60% incidence of deaths. Similar results were obtained after irradiation on day 3.5 of gestation. This reciprocal relationship of radiosensitivity to anomalies and to embryonic or fetal lethality supports the notion that embryonic or fetal tissues have a p53-dependent "guardian" of the tissue that aborts cells bearing radiation-induced teratogenic DNA damage. In fact, after X-irradiation, the number of cells with apoptotic DNA fragments was greatly increased in tissues of the p53+/+ fetuses but not in those of the p53-/- fetuses.
To clarify the relationship between the changes of trabecular bone turnover and bone marrow cell development during mechanical unloading and reloading, we performed experiments with tail-suspended mice. At 8 weeks of age, 150 male ddY mice were divided into three body weight-matched groups. Mice of group 1 were euthanized at the start of tail suspension (day 0) as a baseline control. The mice of group 2 were subjected to hindlimb unloading by tail suspension for 14 days and reloading for the subsequent 14 days. The mice of group 3 were normally loaded as age-matched controls. Mice of groups 2 and 3 were sacrificed at 7, 14, and 28 days after the start of the experiment. In the first experiment (histomorphometric study of tibiae), unloading for 7 and 14 days and reloading for the subsequent 14 days significantly decreased the bone volume compared with that in the age-matched controls, respectively. Unloading for 7 and 14 days also significantly reduced the bone formation rate (BFR/BS), respectively, but reloading for the subsequent 14 days restored BFR/BS to the control level. While the unloading for 7 and 14 days significantly increased both the osteoclast surface (Oc.S/BS) and the osteoclast number (Oc.N/ BS), the reloading for the subsequent 14 days decreased Oc.S/BS and Oc.N/BS, respectively. In the second experiment (bone marrow cell culture study of tibiae), unloading for 7 and 14 days reduced the adherent stromal cell number, without significance. Unloading for 7 days significantly decreased the mineralized nodule formation. Reloading for the subsequent 14 days markedly increased the adherent stromal cell number and the mineralized nodule formation. Unloading for 7 days significantly increased the number of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells. These data clearly demonstrate that unloading reduces bone formation and increases bone resorption, and subsequent reloading restores reduced bone formation and suppresses increased bone resorption, closely associated with the changes in adherent stromal cell number, mineralized nodule formation, and the number of TRAP-positive multinucleated cells. (J Bone Miner Res 1999;14:1596-1604)
In order to evaluate the effects of pulsing electromagnetic fields (PEMFs) on cell proliferation and glycosaminoglycan (GAG) synthesis and to study the action site of PEMF stimulation in the cells, we performed a series of experiments on rabbit costal growth cartilage cells and human articular cartilage cells in culture. A PEMF stimulator was made using a Helmholz coil. Repetitive pulse burst electric currents with a burst width of 76 ms, a pulse width of 230 microseconds and 6.4 Hz were passed through this coil. The magnetic field strength reached 0.4 mT (tesla) on the average. The syntheses of DNA and GAG were measured by 3H-thymidine and 35S-sulfuric acid incorporations. The effects on the cells treated with lidocaine, adriamycin and irradiation were also measured using a colony forming assay. The PEMF stimulation for the duration of 5 days promoted both cell proliferation and GAG synthesis in growth cartilage cells and intermittent stimulation on and off alternatively every 12 h increased them most significantly, while, in articular cartilage cells, the stimulation promoted cell proliferation, but did not enhance GAG synthesis. PEMF stimulation promoted cells treated with lidocaine more significantly than with other agents. These results present evidence that intermittent PEMF stimulation is more effective on both cell proliferation and GAG synthesis of cartilage cells than continuous stimulation, and that the stimulation could exert effects not by nucleus directly, but by the cellular membrane-dependent mechanism. This study provides further basic data to encourage the clinical application of PEMF stimulation on bone and cartilage disorders.
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