We used highly purified avian osteoclasts and isolated membranes from osteoclasts to study effects of tamoxifen, 4-hydroxytamoxifen, calmodulin antagonists, estrogen, diethylstilbestrol, and the anti-estrogen ICI 182780 on cellular degradation of 3 H-labeled bone in vitro and on membrane HCl transport. Bone resorption was reversibly inhibited by tamoxifen, 4-hydroxytamoxifen, and trifluoperazine with IC 50 values of ϳ1 M. Diethylstilbestrol and 17--estradiol had no effects on bone resorption at receptor-saturating concentrations, while ICI 182780 inhibited bone resorption at concentrations greater than 1 M. At these concentrations ICI 182780, like tamoxifen, inhibits calmodulin-stimulated cyclic nucleotide phosphodiesterase activity. Membrane Transport of Ca 2ϩ into and out of bone is critical for maintenance of serum calcium activity. This requires continuous bone turnover at variable rates, which is mediated by the osteoclast. However, skeletal mineral is also structurally vital, so osteoclastic activity is regulated by multiple factors, often acting in opposing directions. Several hormonal signals are involved in this regulation, including peptides and low molecular weight factors (1). Steroids including estrogens have major effects on bone turnover (2), but the receptors and intermediary signaling involved are not established. This study was performed to determine the mechanism of steroid-related effects on central biochemical elements of osteoclastic activity.A limiting biochemical step and the central regulated element of bone turnover is secretion of HCl to dissolve the bone mineral. This is driven by a vacuolar-like H ϩ -ATPase that is highly expressed in a unique osteoclastic organelle, the ruffled membrane (3). Multiple intermediary cell signals influence the activity of acid secretion, but one of critical interest is intracellular calcium activity and the ubiquitous calcium-binding protein, calmodulin. The unique acid-dependent dissolution of calcium salts produces high local extracellular calcium activity (4), which is reflected in an elaborate osteoclastic calcium regulatory mechanism including a calmodulin-dependent calcium ATPase (5), and factors influencing osteoclastic intracellular calcium activity such as matrix attachment (6). The vacuolarlike H ϩ -ATPase driving acid secretion in osteoclasts is also calmodulin-dependent, and osteoclasts concentrate calmodulin at the ruffled membrane (7).The anti-estrogenic compound, tamoxifen, reduces bone turnover (8), suggesting that tamoxifen may be a particularly useful tool to dissect osteoclast control pathways. Tamoxifen, a known calmodulin antagonist (9), is a triphenylethylene derivative with low toxicity and strong antitumor activity, particularly in breast cancer, properties ascribed to its anti-estrogenic activity (10). Tamoxifen may thus regulate osteoclastic activity by either calmodulin or steroid receptor interactions. In contrast to expectations that tamoxifen would cause bone loss because of anti-estrogenic properties (11), it preserves bo...
In practical situations where workers or the general public may be exposed to ionizing radiation, the resulting irradiation is rarely uniform. The risk figures and dose limits recommended by the International Commission on Radiological Protection (ICRP) are based largely on clinical and epidemiological studies of reasonably uniform irradiated organs. The paucity of clinical or experimental data for highly nonuniform exposures has prevented the ICRP from providing adequate recommendations applicable to this practical situation. This weakness has led on a number of occasions to the postulate that highly nonuniform exposures of organs, such as the lung or the skin, could be 100,000 times more carcinogenic than ICRP risk figures would predict. This so-called "hot-particle hypothesis" found little support among reputable radiobiologists, but could not be clearly and definitively refuted on the basis of experiment. An experiment design, based on skin tumour induction in mouse skin, is described which was developed to test the "hot-particle hypothesis." In collaboration with the Radiobiology Department of St. Bartholomew's Hospital Medical College, London, the skin of 1200 SAS/4 male mice has been exposed to a range of uniform and nonuniform sources of the beta emitter 170Th (Emax 1 MeV). Nonuniform exposures were produced using arrays of 32 or 8 2-mm-diameter sources distributed over the same 8-cm2 area as a uniform control source. Average skin doses varied from 2-100 Gy. The results for the nonuniform sources show a 30% reduction in tumour incidence by the 32-point array at the lower mean doses compared with the response from uniform sources. The eight-point array showed an order-of-magnitude reduction in tumour incidence compared to uniform irradiation at low doses. These results, in direct contradiction to the "hot-particle hypothesis," indicate that nonuniform exposures produce significantly fewer tumours than uniform exposures.
A case is presented in which a meningioma and a glioma grew in the region where, 23 years before, a glial tumor had been partially removed and irradiated. The authors suggest that surgical trauma and ionizing radiation may have influenced the tumor's development.
Cranial irradiation induces healthy tissue damage that can lead to neurocognitive complications and negatively impact patient quality of life. One type of damage associated with cognitive impairment is loss of neuronal spine density. Based on developmental and disease studies implicating microglia and complement in dendritic spine loss, we hypothesized that irradiation-mediated spine loss is microglial complement receptor 3 (CR3)-dependent, and associated with late-delayed cognitive deficits. Utilizing a model of cranial irradiation (acute, 10 Gy gamma) in C57BL/6 mice we found that male mice demonstrate irradiation-mediated spine loss and cognitive deficits whereas female mice and CR3 knockout mice do not. Moreover, pharmacological blockade of CR3 with leukadherin-1 (LA1) prevented these changes in irradiated male mice. Interestingly, CR3 KO mice showed reduced behavioral task performance suggesting that CR3 is important for normal learning and memory. Improving our understanding of irradiation-mediated mechanisms and sexual dimorphic responses is essential for the identification of novel therapeutics to reduce irradiation-induced cognitive decline and improve patient quality of life.
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