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)

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA038189-02
Application #
3176255
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1984-06-15
Project End
1987-05-31
Budget Start
1985-06-01
Budget End
1986-05-31
Support Year
2
Fiscal Year
1985
Total Cost
Indirect Cost
Name
University of Washington
Department
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Lee, M Y; Fevold, K L; Muguruma, Y et al. (1997) Conditions that support long-term production of osteoclast progenitors in vitro. Stem Cells 15:340-6
Hayase, Y; Muguruma, Y; Lee, M Y (1997) Osteoclast development from hematopoietic stem cells: apparent divergence of the osteoclast lineage prior to macrophage commitment. Exp Hematol 25:19-25
Lee, M Y; Jonas, M; Lottsfeldt, J L et al. (1996) Ultrastructural characterization of preosteoclasts derived from bone marrow progenitors stimulated by osteoclast colony stimulating factor. Anat Rec 246:176-84
Lee, T H; Fevold, K L; Muguruma, Y et al. (1994) Relative roles of osteoclast colony-stimulating factor and macrophage colony-stimulating factor in the course of osteoclast development. Exp Hematol 22:66-73
Lee, M Y; Fevold, K L; Dorshkind, K et al. (1993) In vivo and in vitro suppression of primary B lymphocytopoiesis by tumor-derived and recombinant granulocyte colony-stimulating factor. Blood 82:2062-8
Povolny, B T; Lee, M Y (1993) The role of recombinant human M-CSF, IL-3, GM-CSF and calcitriol in clonal development of osteoclast precursors in primate bone marrow. Exp Hematol 21:532-7
Lee, M Y; Lottsfeldt, J L; Fevold, K L (1992) Identification and characterization of osteoclast progenitors by clonal analysis of hematopoietic cells. Blood 80:1710-6
Lee, M Y; Fukunaga, R; Lee, T J et al. (1991) Bone modulation in sustained hematopoietic stimulation in mice. Blood 77:2135-41
Lee, M Y; Eyre, D R; Osborne, W R (1991) Isolation of a murine osteoclast colony-stimulating factor. Proc Natl Acad Sci U S A 88:8500-4
Povolny, B; Lee, M; Hall, S (1990) Modulation of tartrate-resistant acid phosphatase expression by calcitriol in CSF-induced macrophage colonies. Exp Hematol 18:283-8

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