Reduced NFAT1 expression is a risk factor for dysfunction of articular chondrocytes and development of osteoarthritis in aged mice

Abstract

metalloproteinase-13 (MMP-13) level and collagen cleavage. In addition the ratio of the TGFb type 1 receptors, ALK1 and ALK5, increases with age. However, there was considerable cell-cell variability in the measured outcomes. The model shows that the main source of this cellular heterogeneity is due to the stochastic nature of cellular damage, as most variability in the model output was seen in the levels of oxidised proteins and AGE products. There was also considerable variability in the time at which damage starts to accrue, and this accounts for the wide variability in the activation of matrix degrading enzymes. The model showed that negative feedback loops in the system are the main contributor to the age-related increase in the ALK1/ALK5 receptor and this also contributes to the age-related increase in MMP-13 and collagen degradation. Conclusions: Age-related changes in cartilage are caused by complex molecular mechanisms responding to different stress signals. There is both a gradual increase in damaged components and a dysregulation in signalling responses with age. Computer modelling is a complementary approach to assist with unravelling this complexity.

FK506 Induces the TGF-β1/Smad 3 Pathway Independently of Calcineurin Inhibition to Prevent Intervertebral Disk Degeneration

“…In vivo and in vitro data ( Wang et al, 2009 , 2014 ; Greenblatt et al, 2013 ; Zhang et al, 2016 ) from both mice and humans provide a compelling evidence for a crucial role for NFAT family members in maintaining cartilage and joint health. These results suggest that NFAT1 is an essential transcriptional regulator of chondrocyte homeostasis in adult articular cartilage.…”