The role of VEGF and VEGF receptors in bone development and homeostasis

The aim of these studies was to define the functions of VEGF in bone development and postnatal homeostasis. To study the role of osteoblast-derived VEGF during bone development, VEGF was conditionally deleted in Osterix-expressing cells by crossing mice carrying floxed VEGF alleles with Osterix-Cre mice. The results indicate that osteoblast-derived VEGF stimulates osteoblast differentiation and proliferation as well as osteoclastogenesis. In addition, VEGF produced by hypertrophic chondrocytes is important for removal of apoptotic chondrocytes and degradation of cartilage matrix during endochondral bone formation.;Interestingly, VEGF conditional knockout mice exhibit a dramatic reduction in postnatal bone density and a great increase in the number of adipocytes in bone marrow. In bone marrow cell cultures, VEGF deficiency results in suppression of osteoblastogenesis and reduced osteoblast precursor number. This effect is cell-autonomous, and loss of VEGF leads to reduced osteoblast proliferation and cellular senescence. Loss of VEGF in the osteoblast lineage enhances adipocyte differentiation in bone marrow cultures. These findings demonstrate that osteoblast-derived VEGF is critical for maintaining bone homeostasis postnatally by controlling osteoblast precursor number and maintaining the balance between osteoblastogenesis and adipogenesis.;To determine whether VEGF exerts effects on bone development and homeostasis via VEGF receptor signaling in osteoblasts, we deleted VEGF receptors VEGFR-1 (Flt-1) and VEGFR-2 (Flk-1) in the osteoblast lineage using the same Cre- loxP gene targeting strategy as for VEGF. Both VEGFR-1 and VEGFR-2 conditional knockout mice exhibit reduced postnatal bone density. Both receptors are found to be required for maintaining the number of osteoblast progenitors. Loss of VEGFR-1 results in reduced osteoblast proliferation and increased apoptosis as well as increased osteoclastogenesis. VEGFR-1 is also found to be required for bone marrow adipogenesis. Loss of VEGFR-2 leads to reduced osteoblast differentiation.;To our knowledge, this is the first study to investigate the role of osteoblast-derived VEGF and VEGF receptor signaling in osteoblasts. The findings demonstrate that VEGF and its receptors play important roles during bone development and homeostasis.