The role of Tribbles 1 and Tribbles 3 in cartilage turnover

Abstract

Arthritis is a term which encompasses a number of diseases characterised by cartilage degradation and joint destruction which represents an enormous and growing healthcare burden. Matrix metalloproteinases (MMPs) are a family of enzymes involved in cleavage of extracellular matrix proteins. They have many roles in both development and normal tissue homeostasis. As well as this they have been shown to be important in a number of diseases, including arthritis. MMP-1 and -13 in particular have been shown to be important in arthritis, due to their ability to cleave type II collagen, a key component of cartilage. A greater understanding of the regulation of these MMPs could lead to the potential for new therapeutic arthritis treatments. Tribbles (Trb) 1-3 are a group of proteins linked with diseases including diabetes, multiple sclerosis and cancer. Trb 1-3 are reported to play a role in regulating many cellular signalling pathways, such as mitogen-activated protein kinase (MAPK), phosphoinositide-3-kinase/Akt (PI3K/Akt) and nuclear factor kappa B (NFκB). These pathways are considered important in mediating gene expression changes, including MMPs. Both Trb1 and Trb3 were shown to regulate MMPs in chondrocytes, with a greater effect being on MMP-13 regulation. Trb1 and Trb3 were both shown to regulate the major MMP transcription factor AP-1, as well as the ATF3 and NFκB transcription factors. Both Trb1 and Trb3 interacted with MAP2Ks MEK1, MKK4, MKK6 and MKK7, and in addition were shown to regulate MAPK activation, with Trb3 protein levels appearing to be affected by MAP2K levels. Trb3 also had the ability to affect both Akt and STAT activation. These data demonstrate that Trb1 and Trb3 can regulate signalling pathways that have the ability to alter MMP expression and transcription factors within chondrocytes. This would suggest that Trb1 and Trb3 have the ability to affect cartilage degradation. This greater understanding of MMP regulation by Trb1 and Trb3 may help in the development of potential future therapeutic targets for arthritic disease.