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.
Highlights
Osteoarthritis (OA) is a spectrum of degenerative disorders that become much more prevalent with age to the extent that 50% of those aged 65 years suffer from the disease globally [1]
We found that with ageing Transforming growth factor β (TGFβ) may lead to a prolonged inflammatory response in older individuals, resulting in more damage than it normally would in a younger individual suggesting a once protective pathway can lead to prolonged damage
TGFβ represses the induction of MMP13 expression by IL-1+oncostatin M (OSM) in chondrocytes via Alk5 signalling
Summary
Osteoarthritis (OA) is a spectrum of degenerative disorders that become much more prevalent with age to the extent that 50% of those aged 65 years suffer from the disease globally [1]. We and others have reported that TGFβ has a protective effect against a multitude of inflammatory stimuli [10,11,12], including interleukin-1 alpha (IL-1α, referred to as IL-1) in combination with oncostatin M (OSM) (cytokines known to be elevated in OA synovial fluid which markedly induce cartilage destruction [13]). This potent inflammatory stimulus promotes the expression of the collagenases, matrix metalloproteinase (MMP) and MMP13, whilst supressing the expression of their endogenous inhibitor, tissue inhibitor of metalloproteinases (TIMP)1 [14]. It counteracts major catabolic genes such as Runt-related transcription factor 2 (RUNX2), a disintegrin and metalloproteinase with thrombospondin
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