1,25-dihydroxyvitamin D (1,25 (OH)2D) has been classically viewed as a calcium regulating agent. It has become increasingly clear, however, that the vitamin may have a much broader spectrum of biological activity, including an important role in promoting hematopoietic differentiation. The hematopoietic system has received particular attention as a target of 1,25(OH)2D, principally because of the ontogenetic relationship of osteoclasts and bone marrow-derived cells. This issue is especially relevant to periodontal disease as the alveolar bone loss responsible for the associated edentulism is a reflection of enhanced osteoclast recruitment and differentiation. It is now evident that the osteclast is a member of the monocyte/macrophage family, although the precise stage(s) in its maturational pathway at which macrophage precursors acquire and/or lose the capacity to differentiate into osteoclasts remains to be established. Because of this ontogenetic relationship, other investigators and we have focused on the capacity of 1,25(OH)2D to induce monocytic differentiation, reasoning that such experiments would shed light on means by which this steroid promotes osteoclastogenesis. These studies have largely involved the use of leukemic cell lines and have consistently demonstrated that 1,25(OH)2D stimulates differentiation along a monocyte/macrophage pathway.
The aim of this proposal is to extend our studies of vitamin D-induced monocyte differentiation from transformed cells to authentic, bone marrow-derived macrophage precursors. There is convincing evidence that 1,25(OH)2D does, in fact, promote differentiation of bone marrow macrophages, and we propose to explore this phenomenon at both the cellular and molecular levels. Thus, we specifically propose to: 1) ASSESS THE MATURATIONAL EFFECTS OF 1,25(OH)2D ON AUTHENTIC BONE MARROW MOs ISOLATED AT VARIOUS STAGES OF DIFFERENTIATION: 2) IDENTIFY SPECIFIC CELLULAR EVENTS IN BONE MARROW MO DIFFERENTIATION AND PROLIFERATION THAT ARE EFFECTED BY 1,25(OH)2D; AND 3) IDENTIFY 1,25(OH)2D-RESPONSIVE GENES EXPRESSED EARLY IN BONE MARROW MO DIFFERENTIATION.
