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

Abstract

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 (TGFβ) can protect against pro-inflammatory cytokine-mediated MMP expression. With age there is a change in the ratio of two TGFβ type I receptors (Alk1/Alk5), a shift that results in TGFβ losing its protective role in cartilage homeostasis. Instead, TGFβ promotes cartilage degradation which correlates with the spontaneous development of OA in murine models. However, the mechanism by which TGFβ protects against pro-inflammatory responses and how this changes with age has not been extensively studied. As TGFβ 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 TGFβ on chondrocytes treated with a pro-inflammatory stimulus required Alk5. Computational modelling revealed two independent mechanisms were needed to explain the crosstalk between TGFβ 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 TGFβ 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 TGFβ as a potential therapy to prevent age-related loss of cartilage and the development of OA.

An integrated in silico-in vitro approach for identification of therapeutic drug targets for osteoarthritis

“…Interestingly, in silico experiments with our model showed that blocking important transducers of inflammation such as the TGF-β-activating kinase (TAK1) or NFKB while activating the PTHrP related pathway could push a hypertrophic-like chondrocyte into transitioning towards a more healthy or anabolic state (Data file S2). Moreoever, other studies have reported that the TGF-β pathway had a protective effect against inflammation (28)(29)(30)(31), a scenario we evaluated with our model too. In silico mimicking the presence of inflammation in a healthy chondrocyte by forcing several inflammation related pathways of the model to be set at their highest values led to 100% of transition towards the diseased hypertrophic state (Fig.…”

Structure-function specialisation of the interfascicular matrix in the human achilles tendon

“…However, TGF-β signalling has also been shown to be dysregulated in several age-associated diseases, including atherosclerosis, neurodegenerative diseases and arthritis, and is upregulated in tendon injury [ 64 , 65 ]. In cartilage, TGF-β switches from a protective to a detrimental role with ageing, which is associated with osteoarthritis development [66] . TGF-β has also been identified as a master regulator of fibrosis [67] , and it is therefore likely that dysregulation of TGF-β signalling in the old Achilles drives the increase in fibrosis-associated proteins within the IFM.…”

Structure-function Specialisation of the Interfascicular Matrix in the Human Achilles Tendon

“…However, TGF-β signalling has also been shown to be dysregulated in several age-associated diseases, including atherosclerosis, neurodegenerative diseases and arthritis, and is upregulated in tendon injury,[46, 47]. In cartilage, TGF-β switches from a protective to a detrimental role with ageing, which is associated with osteoarthritis development,[48]. It is possible that dysregulation of TGF-β signalling in the old Achilles drives the changes in the IFM proteome that we report here.…”