A potential mode of action for Anakinra in patients with arthrofibrosis following total knee arthroplasty.

David Dixon,Lee A Borthwick,Derek A Mann,Jonathon Coates,Nicole Abdul,Joanna Horabin,Alicia Del Carpio Pons,David J Weir,Nicholas S Kalson,Andrew Walker,Nigel T Brewster,David J Deehan

doi:10.1038/srep16466

David Dixon, Lee A Borthwick + Show 10 more

Open Access

https://doi.org/10.1038/srep16466

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Journal: Scientific reports	Publication Date: Nov 10, 2015
Citations: 30	License type: CC BY 4.0

Affiliation: Newcastle University, Freeman Hospital

Abstract

Arthrofibrosis is a fibroproliferative disease characterised by excessive deposition of extracellular matrix components intra-articularly leading to pain and restricted range of movement. Although frequently observed following total knee arthroplasty (TKA) no therapeutic options exist. A pilot study demonstrated that intra-articular injection of Anakinra, an IL-1R antagonist, improved range of movement and pain in patients with arthrofibrosis however the mechanism of action is unknown. We hypothesise that IL-1α/β will drive an inflammatory phenotype in fibroblasts isolated from the knee, therefore identifying a potential mechanism of action for Anakinra in arthrofibrosis following TKA. Fibroblasts isolated from synovial membranes and infra-patellar fat pad of patients undergoing TKA express high levels of IL-1R1. Stimulation with IL-1α/β induced a pro-inflammatory phenotype characterised by increased secretion of GMCSF, IL-6 and IL-8. No significant difference in the inflammatory response was observed between fibroblasts isolated from synovial membrane or infra-patellar fat pad. IL-1α/β treatments induced a pro-inflammatory phenotype in fibroblasts from both synovial membrane and infra-patellar fat pad and therefore Anakinra can likely have an inhibitory effect on fibroblasts present in both tissues in vivo. It is also likely that fibroblast responses in the tissues are controlled by IL-1α/β availability and not their ability to respond to it.

Highlights

Developed arthrofibrosis following Total knee arthroplasty (TKA) improvement range of motion and pain with 75% of patients able to return to prior activity levels[8]
In this study we demonstrate that fibroblasts isolated from the infrapatellar fat pad and synovial membrane express high levels of IL-1R1 on their cell surface and adopt a highly inflammatory phenotype in response to stimulation with IL-1α or IL-1β
The expression of mesenchymal markers, fibronectin and vimentin, was confirmed in n = 5 sets of patient cells by Western blotting (Fig. 1b, Supplementary Figure 2b). These data confirm that the cells isolated from the infra-patellar fat pad and synovial membrane represent a uniform population of fibroblasts/mesenchymal cells

Summary

Introduction

Developed arthrofibrosis following TKA improvement range of motion and pain with 75% of patients able to return to prior activity levels[8]. The role of the fibroblast as the major fibrogenic cell is well characterised, less is known about the potential for these cells to contribute to inflammatory responses. Published work from our laboratory has shown that human lung fibroblasts express high levels of IL-1R1 and are induced to adopt a highly inflammatory phenotype in response to ligation of IL-1R1. Unterhauser et al have reported a 10 fold increase in the frequency of α -SMA containing contractile fibroblastic cells in knee arthrofibrotic tissue after anterior crucial ligament reconstruction[13] suggesting a potentially important role for these cells in the pathophysiology of arthrofibrosis. In this study we demonstrate that fibroblasts isolated from the infrapatellar fat pad and synovial membrane express high levels of IL-1R1 on their cell surface and adopt a highly inflammatory phenotype in response to stimulation with IL-1α or IL-1β. We hypothesise the blockade of IL-1R1 on fibroblasts as a potential mode of action for Anakinra in patients with arthrofibrosis

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