Colony-stimulating factor-1 injections improve but do not cure skeletal sclerosis in osteopetrotic (op) mice.

Abstract

The osteopetrotic (op) mutation in mice is characterized by general skeletal sclerosis; reduced numbers of osteoclasts, macrophages, and monocytes; and failure to be cured by bone marrow transplantation. This mutation 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. Contrary to previous reports, we have noted persistent metaphyseal sclerosis in op mice treated with CSF-1 at doses above physiological concentrations of circulating CSF-1. We pursued this observation by quantitating osteoclasts and macrophages in the first 500 microns (area A) and the subsequent 1000 microns (area B) in the proximal tibial metaphysis using tartrate-resistant acid phosphatase and F4/80 as cell markers. In untreated normal mice, osteoclasts and macrophages were found in areas A (9.1 and 13.8 cells/1000 microns2) and B (4.1 and 9.4 cells/1000 microns2), 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 and macrophages increased significantly in area B. However, area A remained sclerotic, with few macrophages (3% to 20%), and although osteoclast numbers were normal, their distribution was not, being absent in subepiphyseal sites. High CSF-1 gene expression occurs at bone modeling sites, co-localizes with osteoblasts, and temporally correlates with their differentiation.(ABSTRACT TRUNCATED AT 250 WORDS)