Abstract

The mechanism of regulation of osteoclast differentiation of multilineage hematopoietic stem cells, if elucidated, may provide a rationale basis for the treatment of growth deformities and also for treatment of disorders of abnormal bone resorption such as osteopetrosis, periodontal disease and osteoporosis. The applicant will test the hypothesis that the mechanisms of marrow stromal regulation of osteoclastogenesis are juxtacrine and paracrine.
In Specific Aim 1 a, the phenotype of the osteoclast progenitor cell and its regulation by soluble factors including granulocyte-macrophage colony stimulatory factor (GM-CSF), interleukin (IL-1), interleukin-6) and interleukin-11 (IL-11), and by matrix proteins including osteocalcin and osteopontin, will be defined. The applicant will examine the sequence of expression of critical receptors as well as typical osteoclast phenotypic markers.
Specific Aim 1 b will test the regulatory effects of soluble factors such as monocyte colony stimulatory factor (M-CSF), GM-CSF, IL-3, IL-6 and IL-11, and bone matrix components, osteocalcin and osteopontin, and other RGD-containing proteins on osteoclastic differentiation of purified SCA1+Lin-Thy1 low murine hematopoietic stem cells, or progenitorline 32D.
In Specific Aim 2 the mechanism by which stromal cells of the hematopoietic microenvironment influence osteoclastogenesis will be defined by determining the mechanism of action of parathyroid hormone and 1,25-dihydroxyvitamin D3 stimulation of osteoclastogenesis through the stromal cell line GBLneor. The hypothesis is that marrow stromal cells modulate osteoclastogenesis by two mechanisms, one juxtacrine and the other by mediating hormonal effects.
In Specific Aim 3, cure of osteopetros is by correction of the M-CSF/c-fms juxtacrine defect in clonal stromal cell lines of the op/op mouse in vitro, and mutant mice, in vivo, will test the hypothesis that the defect in the hematopoietic microenvironment of the op/op osteopetrotic mutant is corrected by replacement of cell surface m- CSF.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
2R01DE008798-06
Application #
2130196
Study Section
Oral Biology and Medicine Subcommittee 1 (OBM)
Project Start
1988-12-01
Project End
1997-01-31
Budget Start
1994-02-01
Budget End
1995-01-31
Support Year
6
Fiscal Year
1994
Total Cost
Indirect Cost

  Institution

Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115

  Publications

Pogue-Geile, K L; Greenberger, J S (2000) Effect of the irradiated microenvironment on the expression and retrotransposition of intracisternal type A particles in hematopoietic cells. Exp Hematol 28:680-9
Goltry, K L; Epperly, M W; Greenberger, J S (1998) Induction of serum amyloid A inflammatory response genes in irradiated bone marrow cells. Radiat Res 149:570-8
Glowacki, J; Mizuno, S; Greenberger, J S (1998) Perfusion enhances functions of bone marrow stromal cells in three-dimensional culture. Cell Transplant 7:319-26
Mizuno, S; Glowacki, J (1996) Three-dimensional composite of demineralized bone powder and collagen for in vitro analysis of chondroinduction of human dermal fibroblasts. Biomaterials 17:1819-25
Mizuno, S; Glowacki, J (1996) Chondroinduction of human dermal fibroblasts by demineralized bone in three-dimensional culture. Exp Cell Res 227:89-97
Gerstenfeld, L C; Uporova, T; Schmidt, J et al. (1996) Osteogenic potential of murine osteosarcoma cells: comparison of bone-specific gene expression in in vitro and in vivo conditions. Lab Invest 74:895-906
Goff, J P; Shields, D S; Petersen, B E et al. (1996) Synergistic effects of hepatocyte growth factor on human cord blood CD34+ progenitor cells are the result of c-met receptor expression. Stem Cells 14:592-602
Jahroudi, N; Ardekani, A M; Greenberger, J S (1996) Ionizing irradiation increases transcription of the von Willebrand factor gene in endothelial cells. Blood 88:3801-14
Greenberger, J S; Anderson, J; Berry, L A et al. (1996) Effects of irradiation of CBA/CA mice on hematopoietic stem cells and stromal cells in long-term bone marrow cultures. Leukemia 10:514-27
Pogue-Geile, K; Sakakeeny, M A; Panza, J L et al. (1995) Cloning and expression of unique murine macrophage colony-stimulating factor transcripts. Blood 85:3478-86

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