The proposed studies will analyze osteoclast generation and function in animals and humans with osteopetrosis. Osteoclast generation will be studied to elucidate: (1) the cell of origin, (2) the cellular microenvironment necessary to support generation, (3) the sequence of cellular events occurring in bone during osteoclast generation. The ability of calcitriol and heparin to stimulate normal and osteopetrotic bone resorption will be quantitated. Based on these results, therapy with these stimulants will be assessed in four osteopetrotic rodent mutants. These therapies will be compared to standard transplantation of marrow stem cells, as well as new transplantation techniques using enriched and/or stimulated stem cell populations. Assays will be devised to measure osteoclast generation and bone resorptive function in vitro. The clinical application of these assays will be tested. This knowledge base will be utilized to improve therapy for patients with osteopetrosis. The overall objective is to provide new therapies and assays which can be applied both to the treatment of patients with osteopetrosis, as well as to other metabolic bone diseases.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
1P01HD019767-01
Application #
3096888
Study Section
Maternal and Child Health Research Committee (HDMC)
Project Start
1985-05-01
Project End
1988-04-30
Budget Start
1985-05-01
Budget End
1986-04-30
Support Year
1
Fiscal Year
1985
Total Cost
Indirect Cost
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
Greenberger, J S; FitzGerald, T J; Anklesaria, P (1989) Recent studies of the hematopoietic microenvironment in long-term bone marrow cultures. Immunol Res 8:226-35
Glowacki, J; Cox, K A; Wilcon, S (1989) Impaired osteoclast differentiation in subcutaneous implants of bone particles in osteopetrotic mutants. Bone Miner 5:271-8
Ohta, M; Anklesaria, P; FitzGerald, T J et al. (1989) Long-term bone marrow cultures: recent studies with clonal hematopoietic and stromal cell lines. Pathol Immunopathol Res 8:1-20
Ohta, M; Anklesaria, P; Wheaton, M et al. (1989) Retroviral src gene expression in continuous marrow culture increases the self-renewal capacity of multilineage hematopoietic stem cells. Leukemia 3:206-26
FitzGerald, T J; Santucci, M A; Harigaya, K et al. (1988) Radiosensitivity of permanent human bone marrow stromal cell lines: effect of dose rate. Int J Radiat Oncol Biol Phys 15:1153-9
Shapiro, F (1988) Cortical bone repair. The relationship of the lacunar-canalicular system and intercellular gap junctions to the repair process. J Bone Joint Surg Am 70:1067-81
Greenberger, J S; FitzGerald, T J; Klassen, V et al. (1988) Alteration in hematopoietic stem cell seeding and proliferation by both high and low dose rate irradiation of bone marrow stromal cells in vitro. Int J Radiat Oncol Biol Phys 14:85-94
FitzGerald, T J; Anklesaria, P; Le, D et al. (1988) Radiosensitivity of cloned permanent murine bone marrow stromal cell lines: nonuniform effect of low dose rate. Exp Hematol 16:820-6
Shapiro, F (1987) Epiphyseal disorders. N Engl J Med 317:1702-10
Anklesaria, P; Sakakeeny, M A; Klassen, V et al. (1987) Expression of a selectable gene transferred by a retroviral vector to hematopoietic stem cells and stromal cells in murine continuous bone marrow cultures. Exp Hematol 15:195-202

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