How vascular endothelial growth factor-A (VEGF) regulates differentiation of mesenchymal stem cells

Abstract

Vascular endothelial growth factor A (VEGF), a key factor in angiogenesis, plays an essential role in skeletal development and postnatal homeostasis. VEGF serves as a survival factor for chondrocytes and couples the resorption of cartilage with bone formation during endochondral ossification. Recently, it has also been found to regulate the balance between osteoblast and adipocyte differentiation in bone marrow mesenchymal stem cells. Surprisingly, this regulatory function of VEGF is not based on paracrine signaling involving cell surface receptor activation. Instead, the mechanism appears to utilize intracellular VEGF, which is functionally linked to the nuclear envelope protein lamin A. Lamin A and VEGF control osteoblast and adipocyte differentiation by regulating the levels of the osteoblast and adipocyte transcription factors Runx2 and PPARγ, respectively. These data raise the intriguing possibility that loss of bone mass during aging may be manipulated by controlling the levels and activity of intracellular VEGF in bone marrow mesenchymal stem cells.

Keywords: VEGF; bone remodeling; osteoblast; skeletal development; transcription.

Figure 1.

Diagram illustrating the stages of endochondral ossification and the expression of VEGF during the process. First expressed by cells in mesenchymal condensations and in perichondrial cells of avascular cartilage models of the future bone, VEGF is highly expressed by hypertrophic chondrocytes. This high level of expression stimulates the invasion of endothelial cells, osteoclasts, osteoblastic progenitor cells and hematopoietic cells into the hypertrophic cartilage during the formation of the primary ossification center.

Figure 2.

Diagram illustrating how Osterix-expressing osteoblast progenitor cells in the perichondral region of endochondral bones respond to VEGF produced by hypertrophic chondrocytes during endochondral ossification.

Figure 3.

(A) Section of the femur from a 2 month-old wild type mouse. (B) Section of the femur from a mouse with a conditional loss of VEGF expression in Osterix-expressing osteoblastic cells. The loss of VEGF expression is associated with decreased trabecular and cortical bone mass and an increased number of adipocytes in the bone marrow. Scale bars = 1 mm.

Figure 4.

Diagram illustrating how VEGF, produced by osteoblast progenitor cells, serves to stimulate osteoblast differentiation via an intracrine mechanism but stimulates osteoclastogenesis and angiogenesis as a paracrine factor. Neutralizing antibodies against VEGF can inhibit the paracrine function of VEGF but not its intracrine function.

Figure 5.

Confocal microscopy of bone marrow-derived mesenchymal stem cells stained with (A) non-immune IgG or (B) antibodies against VEGF. Staining shows reactivity in both the endoplasmic reticulum/Golgi and the nucleus. DAPI nucleic acid stain was used to stain cell nuclei. Scale bar = 10 µm.