The effects of vitamin D binding protein-macrophage activating factor and colony-stimulating factor-1 on hematopoietic cells in normal and osteopetrotic rats

Abstract

Osteopetrosis is a heterogeneous group of bone disorders characterized by the failure of osteoclasts to resorb bone and by several immunological defects including macrophage dysfunction. Two compounds, colony-stimulating factor-1 (CSF-1) and vitamin D-binding protein-macrophage activating factor (DBP-MAF) were used in the present study to evaluate their effects on the peritoneal population of cells and on cells within the bone marrow microenvironment in normal and incisors absent (ia) osteopetrotic rats. Previous studies in this laboratory have demonstrated that administration of DBP-MAF to newborn ia animals results in a substantial increase in bone marrow cavity size due to upregulated osteoclast function. To study the effects of these compounds on the macrophage/osteoclast precursors, DBP-MAF, CSF-1, and the combination of these compounds were given to newborn ia and normal littermate animals. Both the normal and mutant phenotypes responded similarly when treated with these compounds. Rats exhibited a profound shift toward the macrophage lineage from the neutrophil lineage when compared with vehicle-treated control animals after treatment with these compounds. In the in vivo peritoneal lavage study, animals received injections of CSF-1, DBP-MAF or DBP-MAF/CSF-1 over a 4-week period. The various types of cells in the peritoneal cavity were then enumerated. The in vitro study consisted of cells isolated from the bone marrow microenvironment and cultured on feeder layers of CSF-1, DBP-MAF, or DBP-MAF/CSF-1 for colony enumeration. The increase in macrophage numbers at the expense of neutrophil numbers could be seen in both the in vivo and in vitro experiments. The macrophage/osteoclast and neutrophil lineages have a common precursor, the granulocyte/macrophage colony-forming cell (GM-CFC). With the addition of CSF-1, the GM-CFC precursor may be induced into the macrophage/osteoclast lineage rather than the granulocyte lineage. This increased pool of cells in the macrophage/osteoclast lineage can be functionally upregulated with the subsequent addition of DBP-MAF to perform the activities of phagocytosis and bone resorption. The in vitro data also showed that DBP-MAF did not support colony development as in CSF-1 or the combination treatment. The recruitment and activation of cells into the macrophage/ osteoclast lineage may help to correct the bone and immune defects found in diseases demonstrating a significant lack of myeloid cells, as well as neutrophilia disorders and the disease, osteopetrosis.

Association of Molecular Variants, Haplotypes, and Linkage Disequilibrium Within the Human Vitamin D-Binding Protein (DBP) Gene With Postmenopausal Bone Mineral Density

“…(15) In vitro studies have suggested that DBP may also mediate differentiation of hematopoietic cells and generate osteoclasts directly. (14,16,17) In view of these features, we considered the DBP gene to be a highly likely candidate for involvement in susceptibility to osteoporosis. In the work reported here, we examined the potential involvement of the DBP gene in the pathogenesis of osteoporosis by investigating genetic variations, constructing haplotypes, analyzing linkage disequilibrium among the variations, and carrying out multiple regression analyses to examine possible associations with BMD in 384 adult women.…”

“…This receptor takes up DBP‐bound vitamin D in urine for reabsorption into epithelial cells in proximal renal tubules (15) . In vitro studies have suggested that DBP may also mediate differentiation of hematopoietic cells and generate osteoclasts directly (14,16,17) . In view of these features, we considered the DBP gene to be a highly likely candidate for involvement in susceptibility to osteoporosis.…”

Establishment of In Vitro and In Vivo Anticolorectal Cancer Efficacy of Lithocholic Acid-Based Imidazolium Salts

“…LCA is an interesting pharmacological compound due to its antibacterial, antifungal activities, and inhibition of α-2,3-sialyltransferase [19][20][21][22][23]. The pharmacological interest in lithocholic acid is associated with the effective induction of vitamin D receptor (VDR) expression [24] and the demonstration of anticancer activity [25,26].…”