title: Mathematical modelling of cytokines, MMPs and fibronectin fragments in osteoarthritic cartilage.
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.
authors.affiliation: School of Computer Science, University of Nottingham, Nottingham, UK. michelle.baker@nottingham.ac.uk.
authors.forename: Michelle
authors.identifier: 0000-0002-8926-7689
authors.initials: M
authors.lastname: Baker
authors.affiliation: Centre for Mathematical Medicine and Biology, School of Mathematical Sciences, University of Nottingham, Nottingham, UK.
authors.forename: Bindi S
authors.initials: BS
authors.lastname: Brook
authors.affiliation: Centre for Mathematical Medicine and Biology, School of Mathematical Sciences, University of Nottingham, Nottingham, UK.
authors.forename: Markus R
authors.initials: MR
authors.lastname: Owen
mesh_terms: D002358:Cartilage, Articular / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D025461:Feedback, Physiological; D005353:Fibronectins / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000209:etiology / Q000378:metabolism / Q000628:therapy; D055641:Mathematical Concepts; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D008954:Models, Biological; D010003:Osteoarthritis / Q000209:etiology / Q000378:metabolism* / Q000628:therapy; D010446:Peptide Fragments / Q000378:metabolism
chemical_list: D016207:Cytokines; D005353:Fibronectins; D010446:Peptide Fragments; D020782:Matrix Metalloproteinases
keywords: Cytokine; Modelling; Non-linear dynamics; Osteoarthritis; Simulation