Macrophage Differentiation in Osteopetrotic Mice (OP／OP）Defective in the Production of Macrophage Colony-Stimulating Factor （M-CSF／CSF-1）

"Osteopetrotic（OP／OP） mouse is an animal model for osteopetrosis and was demonstrated to be a mutation within the coding region of M－CSF gene itself. The OP／OP mouse serves as a model for investigating the differentiation mechanism of macrophage populations in the absence of functional M－CSF. The OP／OP mice also provide evidence to show the role of M-CSF in physiological and pathological conditions. The OP／OP mice are severely monocytopenic and show marked reduction and abnormal differentiation of tissue macrophages and osteoclasts. Most of these macrophages are ultrastructurally immature. Compared with the tissues of normal littermates, those of mutants contained about 30％ of macrophages in many tissues, suggesting that the heterogeneity of macrophages is generated by their different dependency to M－CSF. In contrast, the numbers of dendritic cells in the epidermis and lymphoid apparatus of OP／OP mice were not reduced comparing to those in normal littermates, indicating that dendritic cells are an M－CSF－independent population. After daily M-CSF injection the numbers of monocytes, tissue macrophages, and osteoclasts showed remarkable increases and macrophages demonstrated morphological maturation. However, the numbers of macrophages in the ovary and uterus were not increased. After glucan injection hepatic granulomas in OP/OP mice were formed but smaller, less numerous, and more irregular in shape than those of normal littermates. Kupffer cells in the mutant mice exhibited an active proliferation capacity, particularly just before the stage of granuloma foration. After administration of M-CSF, numbers of monocytes and Kupffer cells increased rapidly in OP/OP mice and granuloma formation was enhanced in these mice. These results indicate that M-CSF-independent Kupffer cells and M-CSF-dependent macrophage populations play an important role in granuloma formation. In conclusion, M-CSF is an important molecule for proliferation and differentiation of not only M-CSF-dependent macrophages but also M-CSF-independent macrophages in physiological conditions. Furthermore, M-CSF is largely responsible for providing a microenvironment for generating macrophage heterogeneity in vivo.