Fibroblast activation and inflammation in frozen shoulder

Akbar, M. et al. (2019) Fibroblast activation and inflammation in frozen shoulder. PLoS ONE, 14(4), e0215301. (doi: 10.1371/journal.pone.0215301) (PMID:31013287) (PMCID:PMC6478286)

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Introduction: Frozen shoulder is a common, fibro-proliferative disease characterised by the insidious onset of pain and progressively restricted range of shoulder movement. Despite the prevalence of this disease, there is limited understanding of the molecular mechanisms underpinning the pathogenesis of this debilitating disease. Previous studies have identified increased myofibroblast differentiation and proliferation, immune cell influx and dysregulated cytokine production. We hypothesised that subpopulations within the fibroblast compartment may take on an activated phenotype, thus initiating the inflammatory processes observed in frozen shoulder. Therefore, we sought to evaluate the presence and possible pathogenic role of known stromal activation proteins in Frozen shoulder, Methods: Shoulder capsule samples were collected from 10 patients with idiopathic frozen shoulder and 10 patients undergoing shoulder stabilisation surgery. Fibroblast activation marker expression (CD248, CD146, VCAM and PDPN, FAP) was quantified using immunohistochemistry. Control and diseased fibroblasts were cultured for in vitro studies from capsule biopsies from instability and frozen shoulder surgeries, respectively. The inflammatory profile and effects of IL-1β upon diseased and control fibroblasts was assessed using ELISA, immunohistochemistry and qPCR. Results: Immunohistochemistry demonstrated increased expression of fibroblast activation markers CD248, CD146, VCAM and PDPN in the frozen shoulder group compared with control (p < 0.05). Fibroblasts cultured from diseased capsule produced elevated levels of inflammatory protein (IL-6, IL-8 & CCL-20) in comparison to control fibroblasts. Exposing control fibroblasts to an inflammatory stimuli, (IL-1ß) significantly increased stromal activation marker transcript and protein expression (CD248, PDPN and VCAM). Conclusions: These results show that fibroblasts have an activated phenotype in frozen shoulder and this is associated with inflammatory cytokine dysregulation. Furthermore, it supports the hypothesis that activated fibroblasts may be involved in regulating the inflammatory and fibrotic processes involved in this disease.

Item Type:Articles
Glasgow Author(s) Enlighten ID:McInnes, Professor Iain and Garcia Melchor, Dr Emma and Akbar, Mr Moeed and Reilly, Mr James and McLean, Michael and McMillan, Dr Paul and Crowe, Ms Lindsay and Millar, Professor Neal
Creator Roles:
Akbar, M.Conceptualization, Data curation, Formal analysis, Writing – review and editing
McLean, M.Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Writing – review and editing
Garcia-Melchor, E.Data curation, Investigation, Methodology, Writing – review and editing
Crowe, L. A.N.Data curation, Formal analysis
McMillan, P.Data curation, Formal analysis
Reilly, J. H.Data curation, Formal analysis, Investigation, Methodology, Resources, Supervision, Validation
McInnes, I. B.Funding acquisition, Investigation, Validation
Millar, N. L.Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Supervision, Validation, Writing – original draft, Writing – review and editing
Authors: Akbar, M., McLean, M., Garcia-Melchor, E., Crowe, L. A.N., McMillan, P., Fazzi, U. G., Martin, D., Arthur, A., Reilly, J. H., McInnes, I. B., and Millar, N. L.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity
Research Centre:College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Immunobiology
Journal Name:PLoS ONE
Publisher:Public Library of Science
ISSN (Online):1932-6203
Copyright Holders:Copyright © 2019 Akbar et al.
First Published:First published in PLoS ONE 14(4): e0215301
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
632345MRC Doctoral Training Grant 2013/14, 2014/15 and 2015/16George BaillieMedical Research Council (MRC)MR/K501335/1MVLS GRADUATE SCHOOL
3015150Damage mechanisms in tendon diseaseNeal MillarMedical Research Council (MRC)MR/R020515/1III - Immunology
725711HMGB1: a key damage mediator in tendinopathyNeal MillarArthritis Research UK (ARTRESUK)21346III -IMMUNOLOGY