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Intracellular VEGF regulates the balance between osteoblast and adipocyte differentiation
Yanqiu Liu, … , Napoleone Ferrara, Bjorn R. Olsen
Yanqiu Liu, … , Napoleone Ferrara, Bjorn R. Olsen
Published August 13, 2012
Citation Information: J Clin Invest. 2012;122(9):3101-3113. https://doi.org/10.1172/JCI61209.
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Research Article Bone biology Article has an altmetric score of 10

Intracellular VEGF regulates the balance between osteoblast and adipocyte differentiation

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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.

Authors

Yanqiu Liu, Agnes D. Berendsen, Shidong Jia, Sutada Lotinun, Roland Baron, Napoleone Ferrara, Bjorn R. Olsen

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Figure 6

Virus-mediated expression of VEGF rescues osteoblast and adipocyte differentiation in VEGF-deficient cells.

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Virus-mediated expression of VEGF rescues osteoblast and adipocyte diffe...
(A) Infection with VEGF retrovirus (Re-VEGF) rescues the reduction in colony number in CFU-F assays of Vegfafl/fl cells treated with Ad-Cre compared with control retrovirus (Re-GFP). No effect of neutralizing antibody against VEGF (0.8 μg/ml). *P < 0.01, **P < 0.05; n = 3. (B) Decreased number of colonies in CFU-A assays when BMSCs, isolated from Vegfafl/fl mice and treated with Cre adenovirus, are infected with VEGF retrovirus as compared with control retrovirus. *P < 0.05, **P < 0.01; n = 3. (C and D) Reduced number of ALP-positive colonies in CFU-F assays of bone marrow cells from conditional VEGF receptor–knockout mice. (C) Reduced number of colonies with cells from Flt1 mutants. *P < 0.01; n = 3. (D) Reduced number of colonies with cells from Flk1 mutants. *P < 0.01; n = 3. (E and F) Number of adipocyte colonies in CFU-A assays of bone marrow cells from conditional VEGF receptor–knockout mice. (E) Reduced number of colonies with cells from Flt1 mutants. *P < 0.01; n = 3. (F) No changes in colony number with cells from Flk1 mutants.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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