Targeting danger molecules in tendinopathy: the HMGB1/TLR4 axis

Akbar, M. et al. (2017) Targeting danger molecules in tendinopathy: the HMGB1/TLR4 axis. RMD Open, 3(2), e000456. (doi:10.1136/rmdopen-2017-000456) (PMID:28879051) (PMCID:PMC5574425)

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Abstract

Objectives: To seek evidence of the danger molecule, high-mobility group protein B1 (HMGB1) expression in human tendinopathy and thereafter, to explore mechanisms where HMGB1 may regulate inflammatory mediators and matrix regulation in human tendinopathy. Methods: Torn supraspinatus tendon (established pathology) and matched intact subscapularis tendon (representing ‘early pathology’) biopsies were collected from patients undergoing arthroscopic shoulder surgery. Control samples of subscapularis tendon were collected from patients undergoing arthroscopic stabilisation surgery. Markers of inflammation and HMGB1 were quantified by reverse transcriptase PCR (RT-PCR) and immunohistochemistry. Human tendon-derived primary cells were derived from hamstring tendon tissue obtained during hamstring tendon anterior cruciate ligament reconstruction and used through passage 3. In vitro effects of recombinant HMGB1 on tenocyte matrix and inflammatory potential were measured using quantitative RT-PCR, ELISA and immunohistochemistry staining. Results: Tendinopathic tissues demonstrated significantly increased levels of the danger molecule HMGB1 compared with control tissues with early tendinopathy tissue showing the greatest expression. The addition of recombinant human HMGB1 to tenocytes led to significant increase in expression of a number of inflammatory mediators, including interleukin 1 beta (IL-1β), IL-6, IL-33, CCL2 and CXCL12, in vitro. Further analysis demonstrated rhHMGB1 treatment resulted in increased expression of genes involved in matrix remodelling. Significant increases were observed in Col3, Tenascin-C and Decorin. Moreover, blocking HMGB1 signalling via toll-like receptor 4 (TLR4) silencing reversed these key inflammatory and matrix changes. Conclusion: HMGB1 is present in human tendinopathy and can regulate inflammatory cytokines and matrix changes. We propose HMGB1 as a mediator driving the inflammatory/matrix crosstalk and manipulation of the HMGB1/TLR4 axis may offer novel therapeutic approaches targeting inflammatory mechanisms in the management of human tendon disorders.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:McInnes, Professor Iain and Garcia Melchor, Dr Emma and Kitson, Miss Susan and Akbar, Mr Moeed and Reilly, Mr James and Kerr, Mrs Shauna and Crowe, Lindsay and Gilchrist, Dr Derek and Millar, Dr Neal
Authors: Akbar, M., Gilchrist, D. S., Kitson, S. M., Nelis, B., Crowe, L. A.N., Garcia-Melchor, E., Reilly, J. H., Kerr, S. C., Murrell, G. A.C., McInnes, I. B., and Millar, N. L.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:RMD Open
Publisher:BMJ Publishing Group
ISSN:2056-5933
ISSN (Online):2056-5933
Published Online:28 July 2017
Copyright Holders:Copyright © 2017 The Authors
First Published:First published in RMD Open 3(2): e000456
Publisher Policy:Reproduced under a Creative Commons license

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
620681The role of microRNA 29 in tendon diseaseNeal MillarWellcome Trust (WELLCOTR)100651/Z/12/ZIII -IMMUNOLOGY
725711HMGB1: a key damage mediator in tendinopathyNeal MillarArthritis Research UK (ARTRESUK)21346III -IMMUNOLOGY