Heterogeneity of colony stimulating factor-1 gene expression in the skeleton of four osteopetrotic mutations in rats...

Congenital osteopetrosis in mammals is an inherited bone disease caused by aberrations in osteoclast development and/or function. Colony-stimulating factor-1 (CSF-1) promotes formation of osteoclasts and is produced by osteoblasts. Recently, two osteopetrotic mutations (op mouse and tl rat) have been shown to have reductions in CSF-1 activity, and CSF-1 injections improve the skeletal manifestations in each. Several different CSF-1 transcripts have been described in mouse and human soft tissues, and differential expression of CSF-1 transcripts has been documented. Thus, we compared gene expression for CSF-1 as reflected by mRNA levels in the bones of tl rats and op mice, and also two other osteopetrotic rat mutations (ia and op). In op mouse calvaria the 4.6 kb transcript was reduced while the 2.3 kb transcript was absent. However, no differences were detected in the levels of these transcripts in mutant and normal calvaria of tl stock. In contrast, CSF-1 transcript levels were elevated in op rat mutants and variable in ia mutants compared to normal littermates. Osteoblast cultures derived from neonatal animals of tl and op rat stock showed the same differences seen in calvarial bone in vivo. The mRNA expression of another growth factor, TGF-beta 1, paralleled that of CSF-1 in vivo and in vitro in the rat mutations. These data demonstrate the emerging molecular heterogeneity among osteopetrotic mutations and underscore the need to evaluate the contributions of these and other cytokines to osteoclast differentiation and function in each mutation.