Mathematical modelling of cytokines, MMPs and fibronectin fragments in osteoarthritic cartilage

Baker, Michelle; Brook, Bindi S.; Owen, Markus R.

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 upregulator 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.

Citation

Baker, M., Brook, B. S., & Owen, M. R. (2017). Mathematical modelling of cytokines, MMPs and fibronectin fragments in osteoarthritic cartilage. Journal of Mathematical Biology, 75(4), 985-1024. https://doi.org/10.1007/s00285-017-1104-y

• Journal Article Type: Article
• Acceptance Date: Feb 3, 2017
• Online Publication Date: Feb 17, 2017
• Publication Date: 2017-10
• Deposit Date: Feb 8, 2017
• Publicly Available Date: Feb 17, 2017
• Journal: Journal of Mathematical Biology
• Print ISSN: 0303-6812
• Electronic ISSN: 1432-1416
• Publisher: Springer Verlag
• Peer Reviewed: Peer Reviewed
• Volume: 75
• Issue: 4
• Pages: 985-1024
• DOI: https://doi.org/10.1007/s00285-017-1104-y
• Keywords: Osteoarthritis, cytokine, modeling, simulation, non-lineardynamics
• Public URL: https://nottingham-repository.worktribe.com/output/845320
• Publisher URL: http://link.springer.com/article/10.1007%2Fs00285-017-1104-y
• Contract Date: Feb 8, 2017