Increased skeletal VEGF enhances β-catenin activity and results in excessively ossified bones

Abstract

Vascular endothelial growth factor (VEGF) and β‐catenin both act broadly in embryogenesis and adulthood, including in the skeletal and vascular systems. Increased or deregulated activity of these molecules has been linked to cancer and bone‐related pathologies. By using novel mouse models to locally increase VEGF levels in the skeleton, we found that embryonic VEGF over‐expression in osteo‐chondroprogenitors and their progeny largely pheno‐copied constitutive β‐catenin activation. Adult induction of VEGF in these cell populations dramatically increased bone mass, associated with aberrant vascularization, bone marrow fibrosis and haematological anomalies. Genetic and pharmacological interventions showed that VEGF increased bone mass through a VEGF receptor 2‐ and phosphatidyl inositol 3‐kinase‐mediated pathway inducing β‐catenin transcriptional activity in endothelial and osteoblastic cells, likely through modulation of glycogen synthase kinase 3‐β phosphorylation. These insights into the actions of VEGF in the bone and marrow environment underscore its power as pleiotropic bone anabolic agent but also warn for caution in its therapeutic use. Moreover, the finding that VEGF can modulate β‐catenin activity may have widespread physiological and clinical ramifications.

Up-regulation of glycolytic metabolism is required for HIF1α-driven bone formation

“…HIF1α is known to induce VEGFA that activates angiogenesis, and the latter has been postulated to drive ossification in other mouse models (14,23). Moreover, overexpression of an isoform of VEGFA (VEGF164) was reported to cause bone marrow fibrosis similar to what we observed here in the SH−dox mice (24). Therefore, we tested whether VEGFA up-regulation is responsible for the HIF1α-driven bone and fibrosis phenotypes.…”

Osteoblasts in osteoporosis: past, emerging, and future anabolic targets

“…Fibroblast growth factors (FGFs) are other positive regulators of osteoblastogenesis (90), and systemic administration of FGF2 was found to increase bone formation and bone strength in OVX rats (91,92). VEGF can also promote bone formation in vivo (93). However, all the above-mentioned growth factors, despite their potent anabolic effects on bone formation, exert systemic pleiotropic effects and thus may not be suitable in their current forms as systemic therapeutics.…”

Assessment of bone vascularization and its role in bone remodeling

“…Interestingly, canopy cells are in close contact with capillaries and Delaissé 's team recently demonstrated that vessel positioning relative to the bone surface was highly dependent on the remodeling status of the bone remodeling compartment, 13 suggesting substantial vessel plasticity. The complex molecular crosstalk between bone and vascular cells (reviewed in reference 14) is progressively unraveled and includes the cues involved in angiogenesis, such as vascular endothelial growth factor receptor 15 or preosteoclasts/preosteoblasts homing, such as Sphingosine-phosphate 1 concentrations 16 or CXCR4/ CXCL12 signaling, 17,18 which control cell trafficking through the vascular wall.…”