The skeletal effects of colony-stimulating factor-1 in toothless (osteopetrotic) rats: Persistent metaphyseal sclerosis and the failure to restore subepiphyseal osteoclasts

Toothless (tl), one of four osteopetrotic mutations in the rat, is characterized by few osteoclasts, undetectable bone resorption, and failure of correction by bone marrow transplantation. We recently reported that CSF-1 treatment improves these skeletal problems but that metaphyseal sclerosis persists. In the present study we demonstrate that optimal reduction of the skeletal sclerosis in tl rats following CSF-1 treatment has lower and upper dosage thresholds and that skeletal sclerosis returns after CSF-1 withdrawal. Osteoclasts increase significantly in tl rats after CSF-1 treatment, but compared to untreated normal littermates, histochemical staining for characteristic enzymes and osteoclast number is reduced and no osteoclasts appear in the subepiphyseal areas of long bones. These data are interpreted to mean that there are dosage limits to the beneficial skeletal effects of CSF-1, that persistent sclerosis is related to the failure to restore subepiphyseal osteoclasts, that osteoclast or progenitor populations may be deficient or differ in their responses to CSF-1, and that the defect in tl rats is not merely lack of a circulating, biologically active form of CSF-1.