MACROPHAGE DIFFERENTIATION AND GRANULOMATOUS INFLAMMATION IN OSTEOPETROTIC MICE (OP OP) DEFECTIVE IN THE PRODUCTION OF CSF-1/

Since the osteopetrotic (op/op) mouse was demonstrated to have a mutat ion within the coding region of the CSF-1 gene itself, it serves as a model for investigating the differentiation mechanism of macrophage po pulations in the absence of functional CSF-1. The op/op mice were seve rely monocytopenic and showed marked reduction and abnormal differenti ation of tissue macrophages. Osteoclasts as well as marginal metalloph ilic macrophages and marginal zone macrophages in the spleen were abse nt. Most of the tissue macrophages were reduced in number and ultrastr ucturally immature. However, the degree of reduction in numbers of mac rophages in the mutant mice was variable among tissues, suggesting tha t the heterogeneity of macrophages was generated by their different de pendency on CSF-1. After daily CSF-1 injection, the numbers of monocyt es, tissue macrophages, and osteoclasts were remarkably increased, and the macrophages showed morphological maturation. However, the numbers of macrophages in the ovary, uterus, and synovial membrane were not i ncreased. In the bone marrow, macrophage precursors detected by monocl onal antibody ER-MP58 proliferated and differentiated into preosteocla sts and osteoclasts. In the spleen, marginal metallophilic macrophages and marginal zone macrophages developed slowly. In this manner, CSF-1 plays an important role in the development, proliferation, and differ entiation of certain tissue macrophage populations and osteoclasts. In the op/op mice, Kupffer cells proliferated, transformed into epitheli oid cells and multinucleated giant cells, and participated in glucan-i nduced granuloma formation. In CSF-l-treated op/op mice, the process o f granuloma formation was similar to that in normal littermates due to increased monocytopoiesis and monocyte influx into the granulomas. Th ese results indicate that CSF-1 is a potent inducer of the development and differentiation of CSF-1-dependent monocyte/macrophages, and that CSF-l-independent macrophages also play an important role in granulom a formation. (C) 1997 Wiley-Liss, Inc.