Figure 6.

Proposed model of VEGF action in cartilage. VEGF is produced at high levels by hypertrophic chondrocytes where the longer VEGF isoforms become sequestered in the cartilage matrix. Proteases mediating cartilage resorption, such as MMP-9, release bound VEGF that acts upon endothelial cells, chondroclasts/osteoclasts, and osteoblasts, thereby coupling metaphyseal vascularization, cartilage resorption, and bone formation. When the epiphyseal cartilage exceeds a critical size during development, the midst of the growth plate becomes hypoxic, triggering VEGF expression in immature chondrocytes. Soluble VEGF isoforms are critical to diffuse to the perichondrium and stimulate outgrowth of the epiphyseal vascular network and subsequent vascular invasion preceding secondary ossification. In addition, VEGF also regulates chondrocyte development and survival. The VEGF₁₈₈ isoform is insufficient for these functions, due to restricted diffusion capacities and possibly to lack of interaction with NRP-1. Prolif., proliferation; Differ., differentiation.