It was some years ago that we chanced upon the observation that the best way to activate a chondrocyte in its matrix was to subject it to cutting injury. Since this time we and others have identified many signaling pathways that are activated in response to cutting including the ERK, p38, JNK, NFkB, Wnt, PI3K and Src pathways (and most likely others)! The upstream initiators of this injury response include release of growth factors from the pericellular matrix, stimulation of the cell through ion channels e.g. TRPV4 and activation of the primary cilium. Down stream these pathways regulate a number of genes some of which likely promote catabolic activities within the tissue, some of which stimulate neuronal sensitisation and others, which, we speculate, stimulate the tissue to repair. These responses appear to be recapitulated by in vivo injury when the cartilage is subjected to abnormal mechanical load after surgical joint destabilization. Thus pathways that have been explored by crude in vitro models appear to be relevant to in vivo injury response in early disease. The next challenge will be understanding how different joint activities promote activation of specific mechanosensitive pathways to selectively modulate outcome.
Disclosure of Interest None declared