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PMID:22886301

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Citation

Liu, Y, Berendsen, AD, Jia, S, Lotinun, S, Baron, R, Ferrara, N and Olsen, BR (2012) Intracellular VEGF regulates the balance between osteoblast and adipocyte differentiation. J. Clin. Invest. 122:3101-13

Abstract

Osteoporotic bones have reduced spongy bone mass, altered bone architecture, and increased marrow fat. Bone marrow stem cells from osteoporotic patients are more likely to differentiate into adipocytes than control cells, suggesting that adipocyte differentiation may play a role in osteoporosis. VEGF is highly expressed in osteoblastic precursor cells and is known to stimulate bone formation. Here we tested the hypothesis that VEGF is also an important regulator of cell fate, determining whether differentiation gives rise to osteoblasts or adipocytes. Mice with conditional VEGF deficiency in osteoblastic precursor cells exhibited an osteoporosis-like phenotype characterized by reduced bone mass and increased bone marrow fat. In addition, reduced VEGF expression in mesenchymal stem cells resulted in reduced osteoblast and increased adipocyte differentiation. Osteoblast differentiation was reduced when VEGF receptor 1 or 2 was knocked down but was unaffected by treatment with recombinant VEGF or neutralizing antibodies against VEGF. Our results suggested that VEGF controls differentiation in mesenchymal stem cells by regulating the transcription factors RUNX2 and PPARγ2 as well as through a reciprocal interaction with nuclear envelope proteins lamin A/C. Importantly, our data support a model whereby VEGF regulates differentiation through an intracrine mechanism that is distinct from the role of secreted VEGF and its receptors.

Links

PubMed PMC3428080 Online version:10.1172/JCI61209

Keywords

Adipocytes/physiology; Adiposity; Alkaline Phosphatase; Animals; Bone Density; Bone Marrow/pathology; Bone Marrow Cells/metabolism; Bone Marrow Cells/physiology; Cell Differentiation; Cells, Cultured; Colony-Forming Units Assay; Core Binding Factor Alpha 1 Subunit/metabolism; Femur/diagnostic imaging; Femur/pathology; Gene Expression; Gene Expression Regulation; Lamin Type A/metabolism; Male; Mesenchymal Stem Cells/enzymology; Mesenchymal Stem Cells/metabolism; Mesenchymal Stem Cells/physiology; Mice; Mice, Knockout; Osteoblasts/metabolism; Osteoblasts/physiology; Osteogenesis; Osteoporosis/metabolism; Osteoporosis/pathology; PPAR gamma/genetics; PPAR gamma/metabolism; Radiography; Tibia/diagnostic imaging; Tibia/pathology; Vascular Endothelial Growth Factor A/deficiency; Vascular Endothelial Growth Factor A/genetics; Vascular Endothelial Growth Factor A/physiology; Vascular Endothelial Growth Factor Receptor-1/genetics; Vascular Endothelial Growth Factor Receptor-1/metabolism; Vascular Endothelial Growth Factor Receptor-2/genetics; Vascular Endothelial Growth Factor Receptor-2/metabolism

Significance

Annotations

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

MOUSE:VGFR2

located_in

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:VGFR2

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:VGFR2

involved_in

GO:1903010: regulation of bone development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:4422101

P

Seeded From UniProt

complete

MOUSE:VGFR1

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:LMNA

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:LMNA

involved_in

GO:0010628: positive regulation of gene expression

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:LMNA

involved_in

GO:0072201: negative regulation of mesenchymal cell proliferation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:VEGFA

located_in

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:VEGFA

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:VEGFA

involved_in

GO:0045599: negative regulation of fat cell differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1931048

P

Seeded From UniProt

complete

MOUSE:VEGFA

involved_in

GO:0045669: positive regulation of osteoblast differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1931048

P

Seeded From UniProt

complete

MOUSE:VEGFA

involved_in

GO:0048873: homeostasis of number of cells within a tissue

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1931048

P

Seeded From UniProt

complete

MOUSE:VEGFA

involved_in

GO:0060346: bone trabecula formation

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1931048

P

Seeded From UniProt

complete

MOUSE:VEGFA

involved_in

GO:0061430: bone trabecula morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1931048

P

Seeded From UniProt

complete

MOUSE:VEGFA

involved_in

GO:0010629: negative regulation of gene expression

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SP7

located_in

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:VGFR2

acts_upstream_of_or_within

GO:1903010: regulation of bone development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:4422101

P

Seeded From UniProt

complete

MOUSE:VGFR2

part_of

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

part_of:(CL:0002092)

Seeded From UniProt

complete

MOUSE:VGFR2

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

part_of:(CL:0002092)

Seeded From UniProt

complete

MOUSE:LMNA

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:LMNA

acts_upstream_of_or_within

GO:0010628: positive regulation of gene expression

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:LMNA

acts_upstream_of_or_within

GO:0072201: negative regulation of mesenchymal cell proliferation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:VEGFA

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

part_of:(CL:0002092)

Seeded From UniProt

complete

MOUSE:VEGFA

part_of

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

part_of:(CL:0002092)

Seeded From UniProt

complete

MOUSE:VEGFA

acts_upstream_of_or_within

GO:0010629: negative regulation of gene expression

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:VEGFA

acts_upstream_of_or_within

GO:0045599: negative regulation of fat cell differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1931048

P

Seeded From UniProt

complete

MOUSE:VEGFA

acts_upstream_of_or_within

GO:0045669: positive regulation of osteoblast differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1931048

P

Seeded From UniProt

complete

MOUSE:VEGFA

acts_upstream_of_or_within

GO:0048873: homeostasis of number of cells within a tissue

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1931048

P

Seeded From UniProt

complete

MOUSE:VEGFA

acts_upstream_of_or_within

GO:0060346: bone trabecula formation

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1931048

P

Seeded From UniProt

complete

MOUSE:VEGFA

acts_upstream_of_or_within

GO:0061430: bone trabecula morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1931048

P

Seeded From UniProt

complete

Notes

See also

References

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