The long-term objective of this research is to increase our knowledge about physiological interactions between hemopoietic tissue and bone tissue, seeking a possible role of hemopoietic cells in regulation of bone turnover. In this work mechanisms of excessive osteoelastic bone resorption in an animal model with tumor-induced neutrophilia and hypercalcemia will be explored. Possible humoral bone-resorbing agents or hemopoietic stem cell stimulating agent from the tumor tissue will be detected by in vitro bone resorption assays and hemopoietic stem-cell colony assays. The tumor-derived bone resorbing activity and the tumor-derived mitogenic activities for osteogenic cells and granulocyte progenitors will be characterized and their relationships will be examined. Investigations of humoral and cellular mechanisms of bone resorption and hemopoietic simulation in vivo will be carried out by studies of tumor-bearing mouse serum for bone-resorbing activities, by implantation of diffusion chambers containing mouse calvaria in tumor-bearing mice, by transfusions of tumor-bearing mouse serum into osteopetrotic mice, and by suppression of hemopoiesis using suppressive drugs. Investigations of the role of blood flow in hemopoietic cellularity and bone turnover will be carried out by blood flow measurements using microspheres. The role of lymphokines in activation of hemopoietic stem cells and osteoclasts in tumor-bearing mice will be studied by in vivo lymphocyte-depleted mice and in vitro lymphocyte culture experiments. This research will increase our understanding of the mechanisms of how both neutrophilia and hypercalcemia are brought together and whether they are possibly related or not in this tumor-bearing animal. We believe these investigations will provide us with useful information in understanding the pathophysiology of certain tumor-associated hypercalcemia and neutrophilia in man. (M)
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