AGE-RESOLVING OSTEOPETROSIS - A RAT MODEL IMPLICATING MICROPHTHALMIA AND THE RELATED TRANSCRIPTION FACTOR TFE3

Microphthalmia (Mi) is a basic helix-loop-helix-leucine zipper (b-HLH- ZIP) transcription factor implicated in pigmentation, mast cells, and bone development. Two dominant-negative mi alleles (mi/mi and Mi(or)/M i(or)) in mice cause osteopetrosis. In contrast, osteopetrosis has not been observed in a number of recessive mi alleles, suggesting the exi stence of Mi protein partners important in osteoclast function. An ost eopetrotic rat of unknown genetic defect (mib) has been described whos e skeletal sclerosis improves dramatically with age and that is associ ated with pigmentation defects reminiscent of mouse mi alleles. Here w e report that this rat strain harbors a large genomic deletion encompa ssing the 3' half of mi including most of the b-HLH-ZIP region. Osteoc lasts from these animals lack Mi protein in contrast to wild-type rat, mouse, and human osteoclasts. Mi is not detectable in primary osteobl asts. In addition TFE3, a b-HLH-ZIP transcription factor related to Mi , was found to be expressed in osteoclasts, but not osteoblasts, and t o coimmunoprecipitate with Mi. These results demonstrate the existence of members of a family of biochemically related transcription factors that may cooperate to play a central role in osteoclast function and possibly in age-related osteoclast homeostasis.