Osteopetrosis is a heterogeneous group of diseases characterized by a generalized excess accumulation of bone and a variety of immune defects. The incisors absent (ia) rat mutation demonstrates these skeletal defects due to reduced bone resorption. These animals also have immune deficiencies involving their natural killer (NK) cell functions and the inflammation-primed activation of their phagocytes. Macrophages and osteoclasts from ia animals have reduced capacity to generate superoxides. Mutant ia rats demonstrate defects in the cascade involved in the conversion of vitamin D binding protein (DBP) to a potent macrophage activating factor (DBP-MAF). Recently, we demonstrated that a number of factors which regulate immune function, e.g. interleukin-2, 1,25(OH)2D3 and DBP-MAF had beneficial effects on both the skeletal and immune functions in the ia mutation. The proposed studies will: 1. Identify the cells in the bone microenvironment which bind DBP-MAF, 2. define the ability of DBP-MAF to stimulate bone resorption in an in vitro system and characterize its direct and/or indirect effects on bone resorption, 3. examine various forms of activated DBP for bone resorbing activity to determine the structural requirements of the activated protein, 4. determine the most effective dose of DBP-MAF for the treatment of osteopetrosis in the ia mutation, 5. evaluate the combined treatment of colony stimulating factor-1 (CSF-1) and DBP-MAF in the ia mutation and 6. evaluate the long-term effects of the various treatment protocols in the ia mutation. Characterization of the etiology of some forms of osteopetrosis and evaluation of potential means of therapeutic intervention are direct applications of the proposed studies. These treatment protocols could be considered for clinical trials. These studies should yield information regarding the mechanism by which DBP-MAF exerts its effects on osteoclastic bone resorption in general. Furthermore, DBP-MAF, because of its association with inflammation, is an important factor involved in inflammation-mediated bone resorption in diseases such as periodontal disease, osteoarthritis and rheumatoid arthritis. An understanding of the disruption of DBP-MAF in osteopetrosis will aid in the development of means to block its activity in these osteolytic diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE006065-15
Application #
2414685
Study Section
Oral Biology and Medicine Subcommittee 1 (OBM)
Project Start
1981-08-01
Project End
2000-04-30
Budget Start
1997-05-01
Budget End
1998-04-30
Support Year
15
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Northeast Ohio Medical University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
City
Rootstown
State
OH
Country
United States
Zip Code
44272
Schneider, Gary B; Grecco, Kristina J; Safadi, Fayez F et al. (2003) The anabolic effects of vitamin D-binding protein-macrophage activating factor (DBP-MAF) and a novel small peptide on bone. Crit Rev Eukaryot Gene Expr 13:277-84
Popoff, S N; Schneider, G B (1996) Animal models of osteopetrosis: the impact of recent molecular developments on novel strategies for therapeutic intervention. Mol Med Today 2:349-58
Benis, K A; Schneider, G B (1996) The effects of vitamin D binding protein-macrophage activating factor and colony-stimulating factor-1 on hematopoietic cells in normal and osteopetrotic rats. Blood 88:2898-905
Schneider, G B; Benis, K A; Flay, N W et al. (1995) Effects of vitamin D binding protein-macrophage activating factor (DBP-MAF) infusion on bone resorption in two osteopetrotic mutations. Bone 16:657-62
Schneider, G B; Relfson, M (1994) Effects of interleukin-2 on bone resorption and natural immunity in osteopetrotic (ia) rats. Lymphokine Cytokine Res 13:335-41
Schneider, G B; Relfson, M; Langman, C B (1994) Effects of 1,25-dihydroxyvitamin D3 on bone resorption and natural immunity in osteopetrotic (ia) rats. J Bone Miner Res 9:585-91
Schneider, G B; Relfson, M; Ellis, T M (1992) Qualitative defects in natural killer cell function in ia osteopetrotic rats. J Bone Miner Res 7:941-9
Schneider, G B; Relfson, M (1989) Pluripotent hemopoietic stem cells give rise to osteoclasts in vitro: effects of rGM-CSF. Bone Miner 5:129-38
Schneider, G B; Relfson, M (1988) The effects of transplantation of granulocyte-macrophage progenitors on bone resorption in osteopetrotic rats. J Bone Miner Res 3:225-32
Schneider, G B; Relfson, M (1988) A bone marrow fraction enriched for granulocyte-macrophage progenitors gives rise to osteoclasts in vitro. Bone 9:303-8

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