A comparison of bone turnover in athymic (nude) and euthymic mice: biochemical, histomorphometric, bone ash and in vitro studies

Bone turnover in T-cell deficient mice was investigated by comparing parameters of bone physiology in athymic (nude) and euthymic mice. Static and dynamic bone histomorphometry, serum biochemical assays, body weight and tibia length measurements, and bone ash determination were completed in 6- and 12-wk-old athymic (nude) mice (NIH: Swiss nu/nu) and euthymic mice (nu/+) (10 mice/group). In vitro bone resorbing activity stimulated by parathyroid hormone (PTH) or prostaglandin E2 (PGE2) was measured in calvaria of neonatal athymic and euthymic mice. Athymic mice had smaller vertebral tissue area (p less than 0.01), tibia length (p less than 0.001), and less body weight (p less than 0.01) than euthymic mice. The percent double labeled surface (p less than 0.05) and mineralizing perimeter (p less than 0.01) were reduced in athymic as compared to age-matched euthymic mice. Osteoclast number was reduced in the 6-wk athymic mice as compared to 6-wk euthymic mice. Osteoclastic perimeter was reduced in the 12-wk-old mice (athymic and euthymic) as compared to the 6-wk-old mice. Serum calcium was lower at both ages in athymic mice (p less than 0.01) as compared to euthymic mice. Serum alkaline phosphatase levels were reduced (p less than 0.01) in 12-wk-old athymic mice as compared to age-matched euthymic mice, and were greater in 6-wk-old mice than 12-wk-old mice. Athymic mice had greater femur density than euthymic mice (p less than 0.01), and lower (p less than 0.001) percent ash weight of dry bone compared to euthymic mice.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of interleukin-1 alpha and cyclosporin A in vivo and in vitro on bone and lymphoid tissues in mice

The purpose of this study was to investigate the effects of interleukin-1 alpha (IL-1 alpha) infusion and the ability of cyclosporin A (CYA) to alter IL-1 alpha-induced effects on bone in vivo and in vitro and lymphoid organs in vivo. Mice were administered: IL-1 alpha (2, 4, or 6 days), CYA (6 days), or IL-1 alpha and CYA (6 days). Hypercalcemia was induced in mice treated with IL-1 alpha compared to controls and CYA treated mice, and decreased urinary calcium excretion was present in IL-1 alpha and CYA groups. Osteoclastic bone resorption was increased with a resultant loss of total bone area and bone formation (as measured by mineral apposition rate) was decreased in mice infused with IL-1 alpha. Although CYA-treatment increased bone formation as compared to IL-1 alpha-treatment; CYA in combination with IL-1 alpha did not alter the reduction in mineral apposition rate caused by IL-1 alpha, IL-1 alpha also stimulated bone resorption in vitro which was significantly inhibited by cyclosporin A. IL-1 alpha-induced splenic granulopoiesis, peripheral blood neutrophilia, thymic atrophy, and lymphoid hyperplasia in lymph nodes. CYA-treatment resulted histologically in a severe depletion of lymphocytes in the thymus, a moderate depletion of lymphocytes in lymph nodes but no difference in the histology of the spleen compared to controls. In summary, interleukin-1 alpha was effective in stimulating hypercalcemia and bone resorption both in vivo and in vitro but cyclosporin A was effective in inhibiting IL-1 alpha-mediated bone resorption only in vitro. IL-1 alpha also had marked effects on spleen, thymus, and circulating blood cells; however, most parameters were not affected by the concurrent administration of cyclosporin A.     

Quantitative bone histomorphometry in nude mice bearing a human squamous cell lung cancer

We performed quantitative bone histomorphometry on lumbar vertebrae in hypercalcemic tumor-bearing athymic mice carrying a human squamous cell carcinoma. For comparison, studies were also performed in athymic mice that received bovine 1-34 parathyroid hormone (PTH) infusion at the rate of 0.167 micrograms/hr for 7 days. In both the PTH-infused and tumor-bearing animals, percent cortical and total bone areas were significantly reduced as compared to controls, whereas trabecular bone was significantly reduced only in the tumor-bearing animals. Trabecular perimeter lined by osteoclasts was significantly increased in both tumor-bearing (1.7-fold) and PTH-infused animals (2.8-fold) compared to control mice. Trabecular perimeter lined by active osteoblasts was significantly reduced in the tumor-bearing animals (to 42% of control) and unchanged in the PTH-infused animals (97% of control). Tumor-bearing animals had significantly reduced resorptive as well as formative surfaces as compared to the PTH-infused animals. Dynamic histomorphometry revealed a marked reduction in bone formation rate (23% of control) in the tumor-bearing animals. The studies therefore demonstrate a marked inhibition of bone formation associated with increased bone resorption in this model of hypercalcemia of malignancy. These observations are similar to those seen in the human syndrome.