Age-resolving osteopetrosis: a rat model implicating microphthalmia and the related transcription factor TFE3.

TY - JOUR

T1 - Age-resolving osteopetrosis: a rat model implicating microphthalmia and the related transcription factor TFE3.

AU - Weilbaecher, K N

AU - Hershey, C L

AU - Takemoto, C M

AU - Horstmann, Martin

AU - Hemesath, T J

AU - Tashjian, A H

AU - Fisher, D E

PY - 1998/3/2

Y1 - 1998/3/2

N2 - 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.

AB - 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.

KW - Animals

KW - Base Sequence

KW - Basic Helix-Loop-Helix Leucine Zipper Transcription Factors

KW - DNA-Binding Proteins

KW - Gene Expression

KW - Helix-Loop-Helix Motifs

KW - Humans

KW - Leucine Zippers

KW - Mice

KW - Microphthalmia-Associated Transcription Factor

KW - Microphthalmos

KW - Molecular Sequence Data

KW - Osteoblasts

KW - Osteoclasts

KW - Osteopetrosis

KW - RNA, Messenger

KW - Rats

KW - Rats, Mutant Strains

KW - Sequence Alignment

KW - Sequence Homology, Nucleic Acid

KW - Transcription Factors

U2 - 10.1084/jem.187.5.775

DO - 10.1084/jem.187.5.775

M3 - SCORING: Journal article

C2 - 9480987

VL - 187

SP - 775

EP - 785

JO - J EXP MED

JF - J EXP MED

SN - 0022-1007

IS - 5

M1 - 5

ER -