Bone remodeling and macrophage differentiation in osteopetrosis (op) mutant mice defective in the production of macrophage colony-stimulating factor

Mice homozygous for the osteopetrosis top) mutation are characterized by defective differentiation of osteoclasts, monocytes, and tissue macrophages due to a lack of functional macrophage colony-stimulating factor (M-CSF/CSF-1) activity. In young (4-6 week-old) op/op mice, the bone marrow cavities were filled with spongious Lone. In aged (50-72 week-old) op/op mice, the bone marrow cavities were markedly reconstructed and marrow hematopoiesis was expanded. Numbers of osteodasts and bone marrow macrophages in aged op/op mice were increased but most of the osteoclasts were mononuclear cells and showed poorly developed ruffled borders. Lysosomes of bone marrow macrophages were laden with abundant cry stalloid materials in aged op/op mice and aged littermate mice. However, such macrophages were not ob served in young op/op mice nor in young littermates. In contrast to the marked increase in numbers of osteoclasts and macrophages in the bone marrow the number of Kupffer cells in the liver did not increase in aged op/op mice. Kupffer cells in aged op/op mice did not show ultrastructural maturation with aging and contained a few crystalloid structures. M-CSF administration to aged op/op mice induced numerical increases in Kupffer sells and lysosomes in Kupffer cells, disappearance of crystalloid structures in lysosomes of Kupffer cells, and the development of ruffled border in osteoclasts. These findings indicate that M-CSF-independent mechanisms for macrophage and osteoclast development in aged op/op mice are restricted to bone marrow. M-CSF plays important roles in the differentiation of macrophage and osteoclast and the production and function of lysosomes.