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.
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