A. Bartocci

Osteopetrotic (op/op) mutant mice suffer from congenital osteopetrosis due to a severe deficiency of osteoclasts. Furthermore, the total number of mononuclear phagocytes is extremely low in affected mice. Serum, 11 tissues, and different cell and organ conditioned media from op/op mice were shown to be devoid of biologically active colony-stimulating factor 1 (CSF-1), whereas all of these preparations from littermate control +/+ and +/op mice contained the growth factor. The deficiency was specific for CSF-1 in that serum or conditioned media from op/op mice possessed elevated levels of at least three other macrophage growth factors. Partial correction of the op/op defect was observed following intraperitoneal implantation of diffusion chambers containing L929 cells, which in culture produce CSF-1 as their sole macrophage growth factor. No rearrangement of the CSF-1 gene in op/op mice was detected by Southern analysis. However, in contrast to control lung fibroblasts, which contained 4.6- and 2.3-kilobase CSF-1 mRNAs, only the 4.6-kilobase species was detected in op/op cells. An alteration in the CSF-1 gene is strongly implicated as the primary defect in op/op mice because they do not contain detectable CSF-1, their defect is correctable by administration of CSF-1, the op locus and the CSF-1 gene map within the same region of mouse chromosome 3, their CSF-1 mRNA biosynthesis is altered, and the op/op phenotype is consistent with the phenotype expected in a CSF-1 deficient mouse.

Pregnancy results in an elevation in serum and tissue concentrations of the mononuclear phagocytic growth factor, CSF-1 (colony-stimulating factor 1). These increases are associated with an increase in the number of monocytes in the circulation, and with increases in the number of splenic macrophage precursors. In contrast to the approximately 2-fold elevation of the CSF-1 concentrations in serum and most tissues, pregnancy results in a 1,000-fold increase in the concentration of uterine CSF-1. The roughly fivefold elevation in uterine CSF-1 concentration observed at day 5 of pregnancy could be mimicked by administration of chorionic gonadotrophin in intact but not ovariectomized mice. These dramatic changes in uterine CSF-1 concentrations may indicate a role for CSF-1 in the regulation of nonmononuclear phagocytic cell types.

The physiological mechanism of clearance of the mononuclear phagocyte growth factor, colony-stimulating factor 1 (CSF-1), from the circulation of normal mice was investigated by following the fate of a trace amount of i.v. injected 125I-labeled CSF-1. Macrophages selectively cleared CSF-1 by CSF-1 receptor-mediated endocytosis and degraded the growth factor intracellularly. This manner of clearance provides a feedback control mechanism whereby the rate of macrophage production is determined by the number of mature macrophages.