Age-resolving Osteopetrosis: A Rat Model Implicating Microphthalmia and the Related Transcription Factor TFE3

Abstract

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 Mior/Mior) in mice cause osteopetrosis. In contrast, osteopetrosis has not been observed in a number of recessive mi alleles, suggesting the existence of Mi protein partners important in osteoclast function. An osteopetrotic rat of unknown genetic defect (mib) has been described whose skeletal sclerosis improves dramatically with age and that is associated with pigmentation defects reminiscent of mouse mi alleles. Here we report that this rat strain harbors a large genomic deletion encompassing the 3′ half of mi including most of the b-HLH-ZIP region. Osteoclasts from these animals lack Mi protein in contrast to wild-type rat, mouse, and human osteoclasts. Mi is not detectable in primary osteoblasts. In addition TFE3, a b-HLH-ZIP transcription factor related to Mi, was found to be expressed in osteoclasts, but not osteoblasts, and to 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.

Transcription factor MITF regulates cardiac growth and hypertrophy

“…There are several known isoforms of MITF, differing at the NH 2 terminus (Figure 1, A and B). A short form (MITF M) is expressed in melanocytes while the longer isoforms are expressed in other cells, including osteoclasts and mast cells (22). MITF was expressed in cardiomyocytes both in the H9C2 cell line and in rat neonatal primary culture and was detected at the approximate molecular weight of mast cell MITF ( Figure 1D).…”

Structure, function, and regulation of tartrate-resistant acid phosphatase

“…Immediately 5Ј of this element there is an E-box motif (CAnnTG), which we have found is a functional response element for the microphthalmia transcription factor (MiTF). 77 Mutations in the MiTF gene cause osteoclast functional deficiencies 115,121 such as selective downmodulation of both TRAP mRNA expression and TRAP promoter activity in culture-derived osteoclasts. 77 MiTF could interact with PU.1 bound to the adjacent site, because the factors can bind directly to each other.…”

Microphthalamia-associated transcription factor: a critical regulator of pigment cell development and survival

“…Of note, certain nonmelanocyte lineages, such as osteoclasts, are severely abnormal in mice harboring homozygous dominant-negative MITF mutations, but much less affected by null mutations. This effect is likely because of the ability of dominant-negative MITF mutants that titrate out other MiT family members, such as TFE3 in osteoclasts (Weilbaecher et al, 1998(Weilbaecher et al, , 2001Steingrı´msson et al, 2002).…”