Role of the subchondral vascular system in endochondral ossification: endothelial cell-derived proteinases derepress late cartilage differentiation in vitro

Endochondral ossification in growth plates proceeds through several consecu tive steps of late cartilage differentiation leading to chondrocyte hypertr ophy, vascular invasion, and, eventually, to replacement of the tissue by b one. The subchondral vascular system is essential for this process and late chondrocyte differentiation is subject to negative control at several chec kpoints. Endothelial cells of subchondral blood vessels not only are the so urce of vascular invasion accompanying the transition of hypertrophic carti lage to bone but also produce factors overruling autocrine barriers against late chondrocyte differentiation. Here, we have determined that the action of proteases secreted by endothelial cells were sufficient to derepress th e production of the hypertrophy-markers collagen X and alkaline phosphatase in arrested populations of chicken chondrocytes. Signalling by thyroid hor mones was also necessary but endothelial factors other than proteinases wer e not. Negative signalling by PTH/PTHrP- or TGF-beta -receptors remained un affected by the endothelial proteases whereas signalling by FGF-2 did not s uppress, but rather activated late chondrocyte differentiation under these conditions. A finely tuned balance between chondrocyte-derived signals repr essing cartilage maturation and endothelial signals promoting late differen tiation of chondrocytes is essential for normal endochondral ossification d uring development, growth, and repair of bone. A dysregulation of this bala nce in permanent joint cartilage also may be responsible for the initiation of pathological cartilage degeneration in joint diseases. (C) 2001 Elsevie r Science B.V./International Society of Matrix Biology. All rights reserved .