COLONY-STIMULATING FACTOR-I INJECTIONS IMPROVE BUT DO NOT CURE SKELETAL SCLEROSIS IN OSTEOPETROTIC (OP) MICE

The osteopetrotic (op) mutation in mice is characterized by general sk eletal sclerosis; reduced numbers of osteoclasts, macrophages, and mon ocytes; and failure to be cured by bone marrow transplantation. This m utation has been shown to result from an absence of colony-stimulating factor-1 (CSF-1) and reported to be cured by treatment with CSF-1. Co ntrary to previous reports, we have noted persistent metaphyseal scler osis in op mice treated with CSF-1 at doses above physiological concen trations of circulating CSF-1. We pursued this observation by quantita ting osteoclasts and macrophages in the first 500 mu m (area A) and th e subsequent 1000 mu m (areaB) in the proximal tibial metaphysis using tartrate-resistant acid phosphatase and F4/80 as cell markers. In unt reated normal mice, osteoclasts and macrophages were found in areas A (9.1 and 13.8 cells/1000 mu m(2)) and B (4.1 and 9.4 cells/1000 mu m(2 )), respectively. In untreated mutants, osteoclasts and macrophages as percentages of normal were, respectively, 0% and 2% (area A) and 30% and 13% (area B). After CSF-1 treatment (0.15, 0.3, 0.5, and 1.0 x 10( 6) U/day) for 28 days, marrow cavity size and numbers of osteoclasts a nd macrophages increased significantly in area B. However, area A rema ined sclerotic, with few macrophages (3% to 20%), and although osteocl ast numbers were normal, their distribution was not, being absent in s ubepiphyseal sites. High CSF-1 gene expression occurs at bone modeling sites, co localizes with osteoblasts, and temporally correlates with their differentiation. The failure of physiological concentrations of circulating CSF-1 to restore osteoclasts and macrophages and to cure s clerosis in subepiphy-seal areas (A) of op/op mutants suggests that th is factor must be presented locally to certain site-specific osteoclas t and macrophage progenitors by osteoblasts and/or endothelial cells. Furthermore, the presence of osteoclasts in some skeletal sites in unt reated op mice demonstrates that the development of some osteoclasts i s independent of CSF-1.