Endochondral ossification, extracellular matrix (ECM) remodeling and angiogenic switch. (a) The process of endochondral ossification is dependent upon neovascularization. During this process, cartilage is replaced by bone. The differentiation of chondrocytes into hypertrophic chondrocytes is accompanied by the expression of angiogenic growth factors, notably VEGF, allowing vascular invasion of the cartilage. In the diaphysis, this invasion is strictly limited to the front of ossification in the last row of hypertrophic chondrocytes in direct contact with blood vessels. (b) The process of endochondral ossification also depends upon a switch in the expression of ECM molecules. Proliferating chondrocytes express collagen type II, whereas hypertrophic chondrocytes express collagen type X, matrix metalloprotease 13 (MMP13) and high levels of angiogenic growth factors VEGF and CTGF. On the other side of the ossification front, osteoclasts express MMP9, whereas osteoblasts express MMP13 and collagen type I.