Mild osteopetrosis in the microphthalmia-oak ridge mouse: A model for intermediate autosomal recessive osteopetrosis in humans

Mutations at the mouse microphthalmia (mi) locus affect coat color, eye development, and mast cells. The original allele, mi, also shows severe osteopetrosis. Mice homozygous for the microphthalmia-Oak Ridge (Mi(or)) mutation are white, microphthalmic animals with retarded incisor development. To investigate whether this mutation causes osteopetrosis, we examined skeletal tissues of the Mi(or) mouse. A typical osteopetrotic lesion, accumulation of unresorbed primary spongiosa, was found at the metaphyses of long bones and at the costochondral junctions in Mi(or)/Mi(or) mice from 10 days to 37 days of age, whereas no accumulation was seen at the mid- diaphyses in these bones. The osteopetrotic conditions of Mi(or)/Mi(or) mice increased progressively during the first 5 weeks after birth. However, adult Mi(or)/Mi(or) mice 3 months or older showed improvement of the osteopetrotic condition, although the disease was not completely resolved. Ultrastructurally, osteoclasts of Mi(or)/Mi(or) mice had well developed ruffled borders. These results show that the Mi(or) mutation has milder osteopetrotic changes than the original mi mutation, a surprising observation given that both mutations affect the same functional domain of the mi protein, a basic-Helix-Loop-Helix-Zipper transcription factor. The Mi(or) phenotype resembles the intermediate autosomal recessive osteopetrosis in humans.