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PMID:19252502

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Citation

Ishii, KA, Fumoto, T, Iwai, K, Takeshita, S, Ito, M, Shimohata, N, Aburatani, H, Taketani, S, Lelliott, CJ, Vidal-Puig, A and Ikeda, K (2009) Coordination of PGC-1beta and iron uptake in mitochondrial biogenesis and osteoclast activation. Nat. Med. 15:259-66

Abstract

Osteoclasts are acid-secreting polykaryons that have high energy demands and contain abundant mitochondria. How mitochondrial biogenesis is integrated with osteoclast differentiation is unknown. We found that the transcription of Ppargc1b, which encodes peroxisome proliferator-activated receptor-gamma coactivator 1beta (PGC-1beta), was induced during osteoclast differentiation by cAMP response element-binding protein (CREB) as a result of reactive oxygen species. Knockdown of Ppargc1b in vitro inhibited osteoclast differentiation and mitochondria biogenesis, whereas deletion of the Ppargc1b gene in mice resulted in increased bone mass due to impaired osteoclast function. We also observed defects in PGC-1beta-deficient osteoblasts. Owing to the heightened iron demand in osteoclast development, transferrin receptor 1 (TfR1) expression was induced post-transcriptionally via iron regulatory protein 2. TfR1-mediated iron uptake promoted osteoclast differentiation and bone-resorbing activity, associated with the induction of mitochondrial respiration, production of reactive oxygen species and accelerated Ppargc1b transcription. Iron chelation inhibited osteoclastic bone resorption and protected against bone loss following estrogen deficiency resulting from ovariectomy. These data establish mitochondrial biogenesis orchestrated by PGC-1beta, coupled with iron uptake through TfR1 and iron supply to mitochondrial respiratory proteins, as a fundamental pathway linked to osteoclast activation and bone metabolism.

Links

PubMed Online version:10.1038/nm.1910

Keywords

Animals; Base Sequence; Cell Differentiation; Chromatin Immunoprecipitation; Cyclic AMP Response Element-Binding Protein/physiology; DNA Primers; Female; Gene Knockdown Techniques; Iron/metabolism; Mice; Mitochondria/metabolism; Oligonucleotide Array Sequence Analysis; Osteoclasts/cytology; Osteoclasts/metabolism; Reactive Oxygen Species/metabolism; Receptors, Transferrin/biosynthesis; Reverse Transcriptase Polymerase Chain Reaction; Trans-Activators/genetics; Trans-Activators/metabolism; Trans-Activators/physiology; Transcription, Genetic/physiology

Significance

Annotations

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

MOUSE:TNF11

involved_in

GO:0070371: ERK1 and ERK2 cascade

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:TNF11

involved_in

GO:0042327: positive regulation of phosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:TFR1

involved_in

GO:0030316: osteoclast differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:TFR1

involved_in

GO:0045780: positive regulation of bone resorption

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:IREB2

involved_in

GO:0030316: osteoclast differentiation

ECO:0000270: expression pattern evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:TRFE

involved_in

GO:0007015: actin filament organization

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:TRFE

involved_in

GO:0030316: osteoclast differentiation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:TRFE

involved_in

GO:0045893: positive regulation of transcription, DNA-templated

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:TRFE

involved_in

GO:0045780: positive regulation of bone resorption

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:TRFE

involved_in

GO:0070371: ERK1 and ERK2 cascade

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:TRFE

involved_in

GO:0042327: positive regulation of phosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:TRFE

involved_in

GO:2000147: positive regulation of cell motility

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PRGC2

involved_in

GO:0001503: ossification

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PRGC2

involved_in

GO:0006390: mitochondrial transcription

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PRGC2

involved_in

GO:0007015: actin filament organization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PRGC2

involved_in

GO:0010694: positive regulation of alkaline phosphatase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PRGC2

involved_in

GO:0034614: cellular response to reactive oxygen species

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PRGC2

involved_in

GO:0042327: positive regulation of phosphorylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PRGC2

involved_in

GO:0045780: positive regulation of bone resorption

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PRGC2

involved_in

GO:0045672: positive regulation of osteoclast differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PRGC2

involved_in

GO:0045892: negative regulation of transcription, DNA-templated

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PRGC2

involved_in

GO:0045893: positive regulation of transcription, DNA-templated

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PRGC2

involved_in

GO:0060346: bone trabecula formation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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