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PMID:21982707

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Citation

Ferron, M, Boudiffa, M, Arsenault, M, Rached, M, Pata, M, Giroux, S, Elfassihi, L, Kisseleva, M, Majerus, PW, Rousseau, F and Vacher, J (2011) Inositol polyphosphate 4-phosphatase B as a regulator of bone mass in mice and humans. Cell Metab. 14:466-77

Abstract

Osteoporosis is a multifactorial genetic disease characterized by reduction of bone mass due to dysregulation of osteoclast differentiation or maturation. Herein, we identified a regulator of osteoclastogenesis, the murine homolog of inositol polyphosphate 4-phosphatase type IIα (Inpp4bα). Expression of Inpp4bα is detected from early osteoclast differentiation to activation stage. Targeted expression of native Inpp4bα ex vivo repressed whereas phosphatase-inactive Inpp4bα stimulated osteoclast differentiation. Inpp4bα acts on intracellular calcium level that modulates NFATc1 nuclear translocation and activation. In vivo mice deficient in Inpp4b displayed increased osteoclast differentiation rate and potential resulting in decreased bone mass and osteoporosis. Importantly, INPP4B in human was identified as a susceptibility locus for osteoporosis. This study defined Inpp4b as a major modulator of the osteoclast differentiation and as a gene linked to variability of bone mineral density in mice and humans.

Links

PubMed PMC3204353 Online version:10.1016/j.cmet.2011.08.013

Keywords

Animals; Bone Density/physiology; Calcium/metabolism; Cell Differentiation; Down-Regulation; Humans; Mice; NFATC Transcription Factors/metabolism; Osteoclasts/cytology; Osteoclasts/enzymology; Osteoporosis/etiology; Phosphoric Monoester Hydrolases/genetics; Phosphoric Monoester Hydrolases/metabolism; Protein Isoforms/genetics; Protein Isoforms/metabolism; Signal Transduction

Significance

Annotations

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

MOUSE:TNF11

acts_upstream_of_or_within

GO:0055074: calcium ion homeostasis

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:2158925

P

Seeded From UniProt

complete

MOUSE:TNF11

acts_upstream_of_or_within

GO:0045672: positive regulation of osteoclast differentiation

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:102469
MGI:MGI:2158925

P

Seeded From UniProt

complete

MOUSE:NFAC1

acts_upstream_of_or_within

GO:0030316: osteoclast differentiation

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:2158925
MGI:MGI:2158925

P

Seeded From UniProt

complete

MOUSE:NFAC1

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:NFAC1

located_in

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:NFKB1

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:INP4B

enables

GO:0034593: phosphatidylinositol bisphosphate phosphatase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:INP4B

enables

GO:0034594: phosphatidylinositol trisphosphate phosphatase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:INP4B

acts_upstream_of_or_within

GO:0006874: cellular calcium ion homeostasis

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:1100089

P

Seeded From UniProt

complete

MOUSE:INP4B

acts_upstream_of_or_within

GO:0046850: regulation of bone remodeling

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:5297505

P

Seeded From UniProt

complete

MOUSE:INP4B

acts_upstream_of_or_within

GO:0046822: regulation of nucleocytoplasmic transport

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:INP4B

acts_upstream_of_or_within

GO:0045671: negative regulation of osteoclast differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:INP4B

acts_upstream_of_or_within

GO:0045671: negative regulation of osteoclast differentiation

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:102469
MGI:MGI:1100089

P

Seeded From UniProt

complete

MOUSE:NFKB1

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete


See also

References

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