The murine mutation osteopetrosis is in the coding region of the macrophage colony stimulating factor gene.

Mice homozygous for the recessive mutation osteopetrosis (op) on chromosome 3 have a restricted capacity for bone remodelling, and are severely deficient in mature macrophages and osteoclasts. Both cell populations originate from a common haemopoietic progenitor. As op/op mice are not cured by transplants of normal bone marrow cells, the defects in op/op mice may be associated with an abnormal haematopoietic microenvironment rather than with an intrinsic defect in haematopoietic progenitors. To investigate the molecular and biochemical basis of the defects caused by the op mutation, we established primary fibroblast cell lines from op/op mice and tested the ability of these cell lines to support the proliferation of macrophage progenitors. We show that op/op fibroblasts are defective in production of functional macrophage colony-stimulating factor (M-CSF), although its messenger RNA (Csfm mRNA) is present at normal levels. This defect in M-CSF production and the recent mapping of the Csfm structural gene near op on chromosome 3 suggest that op is a mutation within the Csfm gene itself. We have sequenced Csfm complementary DNA prepared from op/op fibroblasts and found a single base pair insertion in the coding region of the Csfm gene that generates a stop codon 21 base pairs downstream. Thus, the op mutation is within the Csfm coding region and we conclude that the pathological changes in this mutant result from the absence of M-CSF.