Roles of Vascular Endothelial Growth Factor in Skeletal Development, Postnatal Homeostasis and Disease

Vascular endothelial growth factor (VEGF), critical for cardiovascular development, is essential for skeletal development, growth and homeostasis. It couples angiogenesis with bone formation, and it stimulates differentiation of chondrocytes, osteoblasts and osteoclasts during development of synovial joints and membranous as well as endochondral bones. Loss of VEGF expression in chondrocytes during development results in increased apoptotic cell death. Loss of trabecular bone with an increase in marrow fat is the consequence of reduced VEGF expression in bone marrow‐derived osteoblastic progenitors in long bones. In endochondral bone development, VEGF has a major role in establishing primary ossification centers within cartilage models of future bones. High expression of VEGF by hypertrophic chondrocytes establishes a VEGF gradient that induces migration of osteoclasts, endothelial cells, preosteoblasts and hematopoietic stem cells from the perichondrium into the center of ossifying cartilage. As the primary ossification center expands, hypertrophic chondrocytes continue to express high levels of VEGF and as osteoclasts, endothelial cells and preosteoblasts continue to invade the VEGF‐rich environment, metaphyseal growth plates are established. VEGF produced by osteoblastic progenitor cells in periosteum and perichondrium of developing membranous and endochondral bones, stimulates angiogenesis and induces differentiation of progenitor cells to preosteoblasts and bone‐forming osteoblasts. The stimulatory effect on angiogenesis in turn results in endothelial‐derived osteogenic factors that may induce periosteal/perichondrial bone formation. In addition, osteoblast lineage cell‐derived VEGF may also induce osteoblast differentiation based on autocrine/intracrine mechanisms involving cytoplasmic and/or nuclear VEGF. Intracellular VEGF functions are made possible by a gene that contains two transcriptional start sites. Transcripts from the downstream site are translated into proteins with a signal peptide, allowing direct entry into the secretory pathway. In contrast, transcripts from the upstream site are translated into proteins that are about twice the size of secreted VEGF. This “long” VEGF is processed in the cytoplasm to forms that can enter the secretory pathway, or high molecular weight forms that are entering the nuclear compartment. VEGF expression by chondrocytes is required for synovial joint development and the timely differentiation of articular chondrocytes. However, in aging joints the growth factor shows its dark side in that increasing expression levels of VEGF in cells of synovial joints stimulate both articular cartilage degeneration and increased joint pain in osteoarthritis. Support or Funding Information NIH‐NIAMS