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PMID:20628571

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Citation

Tokuzawa, Y, Yagi, K, Yamashita, Y, Nakachi, Y, Nikaido, I, Bono, H, Ninomiya, Y, Kanesaki-Yatsuka, Y, Akita, M, Motegi, H, Wakana, S, Noda, T, Sablitzky, F, Arai, S, Kurokawa, R, Fukuda, T, Katagiri, T, Schönbach, C, Suda, T, Mizuno, Y and Okazaki, Y (2010) Id4, a new candidate gene for senile osteoporosis, acts as a molecular switch promoting osteoblast differentiation. PLoS Genet. 6:e1001019

Abstract

Excessive accumulation of bone marrow adipocytes observed in senile osteoporosis or age-related osteopenia is caused by the unbalanced differentiation of MSCs into bone marrow adipocytes or osteoblasts. Several transcription factors are known to regulate the balance between adipocyte and osteoblast differentiation. However, the molecular mechanisms that regulate the balance between adipocyte and osteoblast differentiation in the bone marrow have yet to be elucidated. To identify candidate genes associated with senile osteoporosis, we performed genome-wide expression analyses of differentiating osteoblasts and adipocytes. Among transcription factors that were enriched in the early phase of differentiation, Id4 was identified as a key molecule affecting the differentiation of both cell types. Experiments using bone marrow-derived stromal cell line ST2 and Id4-deficient mice showed that lack of Id4 drastically reduces osteoblast differentiation and drives differentiation toward adipocytes. On the other hand knockdown of Id4 in adipogenic-induced ST2 cells increased the expression of Ppargamma2, a master regulator of adipocyte differentiation. Similar results were observed in bone marrow cells of femur and tibia of Id4-deficient mice. However the effect of Id4 on Ppargamma2 and adipocyte differentiation is unlikely to be of direct nature. The mechanism of Id4 promoting osteoblast differentiation is associated with the Id4-mediated release of Hes1 from Hes1-Hey2 complexes. Hes1 increases the stability and transcriptional activity of Runx2, a key molecule of osteoblast differentiation, which results in an enhanced osteoblast-specific gene expression. The new role of Id4 in promoting osteoblast differentiation renders it a target for preventing the onset of senile osteoporosis.

Links

PubMed PMC2900302 Online version:10.1371/journal.pgen.1001019

Keywords

Animals; Basic Helix-Loop-Helix Transcription Factors/metabolism; Cell Differentiation; Core Binding Factor Alpha 1 Subunit/physiology; Homeodomain Proteins/metabolism; Inhibitor of Differentiation Proteins/genetics; Mice; Mice, Knockout; Osteoblasts/cytology; Osteoblasts/metabolism; Osteoporosis/etiology; Osteoporosis/pathology; Transcription Factors; Up-Regulation

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:HES1

acts_upstream_of_or_within

GO:0006357: regulation of transcription by RNA polymerase II

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:1341884
MGI:MGI:99414
MGI:MGI:99829

P

Seeded From UniProt

complete

MOUSE:ID4

acts_upstream_of_or_within

GO:0001649: osteoblast differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(EMAPA:32782)
  • results_in_acquisition_of_features_of:(CL:0000062)

Seeded From UniProt

complete

MOUSE:ID4

acts_upstream_of_or_within

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:104853
MGI:MGI:1341884
MGI:MGI:99829

P

Seeded From UniProt

complete

MOUSE:ID4

acts_upstream_of_or_within

GO:0045599: negative regulation of fat cell differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • regulates_o_results_in_acquisition_of_features_of:(CL:0000136)

Seeded From UniProt

complete

MOUSE:ID4

enables

GO:0061629: RNA polymerase II-specific DNA-binding transcription factor binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:Q9QUS4

F

Seeded From UniProt

complete

MOUSE:RUNX2

acts_upstream_of_or_within

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:104853
MGI:MGI:1341884
MGI:MGI:99414

P

Seeded From UniProt

complete

MOUSE:HEY2

acts_upstream_of_or_within

GO:0000122: negative regulation of transcription by RNA polymerase II

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:104853
MGI:MGI:99414
MGI:MGI:99829

P

Seeded From UniProt

complete


See also

References

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