The long term objective of this research proposal is to increase our knowledge in physiological interrelationships between hemopoietic tissue and bone tissue, seeking a possible role of hemopoietic cells in regulation of bone turnover. Using an animal del of tumor-induced granulocytosis associated with hypercalcemia, and isolating the more derived humoral factors, the mechanisms of bone resorption in hyperplastic bone arrow will be explored. During the next grant period, the investigation of bone cell stimulating and bone resorbing humoral agents demonstrated from the CE mammary carcinoma cell clones will be investigated for their molecular relationships to granulopoieticc growth factors also elaborated from the tumor, by the use of molecular probes, well as specific antisera of hemopoietic growth factors, conventional biochemical purification procedures and analysis of gene expression. A new method to precisely analyses osteoclast progenitors from the bone marrow in vitro will be established, characterized and utilized for assays of bone resorbing activities. The in vivo function of isolated CE tumor derived bone modulating or granulopoietic factor will be tested in vivo for its ability to care osteopetrosis in mice. The role of the CE mammary carcinoma- derived factor as well as various purified hemopoietic growth factors in bone resorbing process will be explored by in vitro culture experiments using isolated bone forming cells, marrow stromal cells, marrow mononuclear cells and bone particles and the mechanism of growth factor mediated bone resorotion will be dissected. These studies are to disclose many unanswered basic questions about the defect of hemopoietic growth factors on physiology of bone marrow and bone turnover; well as to understand pathophysiology of unexplained hypercalcemia associated with certain tumors.
| Muguruma, Y; Lee, M Y (1998) Isolation and characterization of murine clonogenic osteoclast progenitors by cell surface phenotype analysis. Blood 91:1272-9 |
| Nagahama, S I; Cunningham, M L; Lee, M Y et al. (1998) Normal development of dental innervation and nerve/tissue interactions in the colony-stimulating factor-1 deficient osteopetrotic mouse. Dev Dyn 211:52-9 |
| 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 |
