Systems biology reveals how altered TGFβ signalling with age reduces protection against pro-inflammatory stimuli

Osteoarthritis (OA) is a degenerative condition caused by dysregulation of multiple molecular signalling pathways. Such dysregulation results in damage to cartilage, a smooth and protective tissue that enables low friction articulation of synovial joints. Matrix metalloproteinases (MMPs), especially MMP-13, are key enzymes in the cleavage of type II collagen which is a vital component for cartilage integrity. Transforming growth factor beta (TGF beta) can protect against pro-inflammatory cytokine-mediated MMP expression. With age there is a change in the ratio of two TGF beta type I receptors (Alk1/Alk5), a shift that results in TGF beta losing its protective role in cartilage homeostasis. Instead, TGF beta promotes cartilage degradation which correlates with the spontaneous development of OA in murine models. However, the mechanism by which TGF beta protects against pro-inflammatory responses and how this changes with age has not been extensively studied. As TGF beta signalling is complex, we used systems biology to combine experimental and computational outputs to examine how the system changes with age. Experiments showed that the repressive effect of TGF beta on chondrocytes treated with a pro-inflammatory stimulus required Alk5. Computational modelling revealed two independent mechanisms were needed to explain the crosstalk between TGF beta and pro-inflammatory signalling pathways. A novel meta-analysis of microarray data from OA patient tissue was used to create a Cytoscape network representative of human OA and revealed the importance of inflammation. Combining the modelled genes with the microarray network provided a global overview into the crosstalk between the different signalling pathways involved in OA development. Our results provide further insights into the mechanisms that cause TGF beta signalling to change from a protective to a detrimental pathway in cartilage with ageing. Moreover, such a systems biology approach may enable restoration of the protective role of TGF beta as a potential therapy to prevent age-related loss of cartilage and the development of OA.