Abstract
Osteoarthritis (OA) is a degenerative disease which causes pain and stiffness in joints. OA progresses through excessive degradation of joint cartilage, eventually leading to significant joint degeneration and loss of function. Cytokines, a group of cell signalling proteins, present in raised concentrations in OA joints, can be classified into pro-inflammatory and anti-inflammatory groups. They mediate cartilage degradation through several mechanisms, primarily the up-regulation of matrix metalloproteinases (MMPs), a group of collagen-degrading enzymes. In this paper we show that the interactions of cytokines within cartilage have a crucial role to play in OA progression and treatment. We develop a four-variable ordinary differential equation model for the interactions between pro- and anti-inflammatory cytokines, MMPs and fibronectin fragments (Fn-fs), a by-product of cartilage degradation and up-regulator of cytokines. We show that the model has four classes of dynamic behaviour: homoeostasis, bistable inflammation, tristable inflammation and persistent inflammation. We show that positive and negative feedbacks controlling cytokine production rates can determine either a pre-disposition to OA or initiation of OA. Further, we show that manipulation of cytokine, MMP and Fn-fs levels can be used to treat OA, but we suggest that multiple treatment targets may be essential to halt or slow disease progression.
Highlights
Osteoarthritis (OA) is a degenerative disease of the joints and is a leading cause of disability worldwide
The value of p at the steady state lies within the range of the oscillatory behaviour so it is not clear which behaviour type would be most destructive to the cartilage. These bifurcations suggest that increasing fibronectin fragments (Fn-fs) clearance in an individual could be beneficial, possibly improving the outcome of treatment to reduce cytokine levels since increasing γ f can move the system from persistent inflammation to bistability
It is largely accepted that cytokines, matrix metalloproteinases (MMPs) and fibronectin fragments are key inflammatory mediators in destructive OA mechanisms
Summary
Osteoarthritis (OA) is a degenerative disease of the joints and is a leading cause of disability worldwide. From the model results the authors suggested that cytokine levels in RA were usually in equilibrium and anti TNF-α forced a shift from a disease equilibrium to a healthy equilibrium. Given that anti-cytokine therapies have so far proved unsuccessful in OA we suggest that the cytokine network but its relationship to other factors in OA, such as the waste products of joint damage, may be crucial in perpetuating the feedback networks leading to disease. For this reason, we extend this previous model to include MMPs and Fn-fs and investigate the interactions between these variables.
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