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Role of VEGF in endochondral bone development. A) Around E12 in mice, mesenchymal progenitor cells condense and differentiate into chondrocytes to form the cartilage anlagen that prefigure future bones. B) Around E14, hypertrophic chondrocytes (HC) form in the cartilage center (diaphysis), while cells in the connective tissue surrounding the cartilage (perichondrium) differentiate into osteoblasts. Osteoblasts deposit a mineralized bone matrix called bone collar around the cartilage. C) The primary ossification center (POC) forms when the diaphysis becomes vascularized and is invaded by osteoclasts, which resorb the hypertrophic cartilage, and by osteoblasts, which deposit bone matrix. The net result is replacement of the avascular cartilage anlage by a vascularized long bone. In the metaphysis, hypertrophic cartilage is continually replaced with trabecular bone, a process that relies on VEGF-mediated vascularization. D) Chondrocytes in the center of the avascular termini of the long bones (epiphyses) become hypoxic and express VEGF. E) Around postnatal day 5, epiphyseal vessels are attracted into the cartilage, likely in response to VEGF signals, and this initiates formation of the secondary ossification center (SOC). F) Discrete layers of residual chondrocytes form ‘growth plates’ between the epiphyseal and metaphyseal bone centers to support further postnatal longitudinal bone growth. G) Role of VEGF in orchestrating the development of the primary ossification center: VEGF is produced at high levels by hypertrophic chondrocytes, likely under the control of RUNX2. Endothelial cells, osteoblasts and osteoclasts express VEGF receptors and accumulate in the perichondrium. VEGF induces vascular invasion of the cartilage and may affect the differentiation and function of osteoblasts and osteoclasts. H) Metaphyseal vascularization, cartilage resorption and bone formation are coordinated by VEGF and MMP activity: Hypertrophic chondrocytes express VEGF120, VEGF164 and VEGF188; VEGF164 and VEGF188 are sequestered in the cartilage matrix, but can be released by proteases such as MMP9 to recruit endothelial cells and act upon osteoclasts and osteoblasts; MMP9 also supports cartilage resorption. I) Role of VEGF isoforms in epiphyseal bone development: When the avascular epiphyseal cartilage exceeds a critical size, immature chondrocytes in the center become hypoxic and express VEGF. The soluble VEGF isoforms VEGF120 and VEGF164 diffuse to the periphery to stimulate expansion of the epiphyseal vascular network and its subsequent invasion into the epiphysis at the start of secondary ossification. VEGF164 also promotes survival of hypoxic chondrocytes, and, in conjunction with other factors such as PTHRP, regulates chondrocyte development.

Cartilage. H/E 20× magnification. Contributed by F Farci, MD

Cartilage and Bone Illustration Contributed by B Palmer

Cartilage and Nerves. H/E 4× magnification. Contributed by F Farci, MD