While 1,25-dihydroxyvitamin D (1,25(OH)2D) is classically viewed as a calcitropic hormone, it has become clear, in the past decade, that the biological repertoire of the steroid extends beyond that of regulating circulating calcium. Vitamin D receptors appear almost ubiquitously in human tissues, and the steroid now presents itself as a modulator of cell differentiation. The hematopoietic system has received particular attention as a target of 1,25(OH)2D principally because of the ontogenetic relationship between osteoclasts an members of the monocyte/macrophage family. This issue is particularly relevant to periodontal disease, as the alveolar bone loss responsible for the associated edentulism is a reflection of enhanced osteoclast recruitment and differentiation. Prior to the present funding period, 1,25(OH)2D-induced monocytic maturation was studied principally in transformed cells. The major focus of our efforts was to extend these experiments to authentic bone marrow macrophages, and we found that the steroid targets to macrophage precursors through the differentiation pathway. Most importantly, as pertains to the present proposal, we found that 1,25(OH)2D upregulates the receptor for the macrophage-specific growth and differentiation factor, CSF-1, and is, in fact, the only natural compound known to do so. This observation may have important implications as regards the means by which 1,25(OH)2D promotes monocytic differentiation. Perhaps of greater significance it suggest the possible use of the hormone or structurally related metabolites in states of bone marrow suppression. Thus, we specifically propose to: 1) DETERMINE THE MECHANISM BY WHICH 1,25 (OH)2D ENHANCES CSF-1 RECEPTOR EXPRESSION BY MACROPHAGE PRECURSORS; 2) DETERMINE IF 1,25(OH)2D TREATMENT OF MACROPHAGE PRECURSORS ALTERS, IN VITRO, CSF-1-INDUCED BIOLOGICAL EVENTS, AND 3) DETERMINE THE EFFECTS OF VITAMIN D STEROLS ON CSF-1R EXPRESSION AND CSF-1-INDUCED BIOLOGICAL EVENTS IN VIVO.
