PMID- 28879051
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20231107
IS  - 2056-5933 (Print)
IS  - 2056-5933 (Electronic)
IS  - 2056-5933 (Linking)
VI  - 3
IP  - 2
DP  - 2017
TI  - Targeting danger molecules in tendinopathy: the HMGB1/TLR4 axis.
PG  - e000456
LID - 10.1136/rmdopen-2017-000456 [doi]
LID - e000456
AB  - 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-1beta), 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.
FAU - Akbar, Moeed
AU  - Akbar M
AD  - Institute of Infection, Immunity and Inflammation, College of Medicine, 
      Veterinary and Life Sciences, University of Glasgow, Glasgow, Scotland, UK.
FAU - Gilchrist, Derek S
AU  - Gilchrist DS
AD  - Institute of Infection, Immunity and Inflammation, College of Medicine, 
      Veterinary and Life Sciences, University of Glasgow, Glasgow, Scotland, UK.
FAU - Kitson, Susan M
AU  - Kitson SM
AD  - Institute of Infection, Immunity and Inflammation, College of Medicine, 
      Veterinary and Life Sciences, University of Glasgow, Glasgow, Scotland, UK.
FAU - Nelis, Briana
AU  - Nelis B
AD  - Institute of Infection, Immunity and Inflammation, College of Medicine, 
      Veterinary and Life Sciences, University of Glasgow, Glasgow, Scotland, UK.
FAU - Crowe, Lindsay A N
AU  - Crowe LAN
AD  - Institute of Infection, Immunity and Inflammation, College of Medicine, 
      Veterinary and Life Sciences, University of Glasgow, Glasgow, Scotland, UK.
FAU - Garcia-Melchor, Emma
AU  - Garcia-Melchor E
AD  - Institute of Infection, Immunity and Inflammation, College of Medicine, 
      Veterinary and Life Sciences, University of Glasgow, Glasgow, Scotland, UK.
FAU - Reilly, James H
AU  - Reilly JH
AD  - Institute of Infection, Immunity and Inflammation, College of Medicine, 
      Veterinary and Life Sciences, University of Glasgow, Glasgow, Scotland, UK.
FAU - Kerr, Shauna C
AU  - Kerr SC
AD  - Institute of Infection, Immunity and Inflammation, College of Medicine, 
      Veterinary and Life Sciences, University of Glasgow, Glasgow, Scotland, UK.
FAU - Murrell, George A C
AU  - Murrell GAC
AD  - Department of Orthopaedic Surgery, Orthopaedic Research Institute, St George 
      Hospital Campus, University of New South Wales, Sydney, New South Wales, 
      Australia.
FAU - McInnes, Iain B
AU  - McInnes IB
AD  - Institute of Infection, Immunity and Inflammation, College of Medicine, 
      Veterinary and Life Sciences, University of Glasgow, Glasgow, Scotland, UK.
FAU - Millar, Neal L
AU  - Millar NL
AUID- ORCID: 0000-0001-9251-9907
AD  - Institute of Infection, Immunity and Inflammation, College of Medicine, 
      Veterinary and Life Sciences, University of Glasgow, Glasgow, Scotland, UK.
LA  - eng
GR  - WT_/Wellcome Trust/United Kingdom
PT  - Journal Article
DEP - 20170728
PL  - England
TA  - RMD Open
JT  - RMD open
JID - 101662038
PMC - PMC5574425
OTO - NOTNLM
OT  - HMGB1
OT  - TLR4
OT  - cytokines
OT  - inflammation
OT  - tendinopathy
OT  - translational
COIS- Competing interests: None declared.
EDAT- 2017/09/08 06:00
MHDA- 2017/09/08 06:01
PMCR- 2017/07/28
CRDT- 2017/09/08 06:00
PHST- 2017/03/03 00:00 [received]
PHST- 2017/06/06 00:00 [revised]
PHST- 2017/06/09 00:00 [accepted]
PHST- 2017/09/08 06:00 [entrez]
PHST- 2017/09/08 06:00 [pubmed]
PHST- 2017/09/08 06:01 [medline]
PHST- 2017/07/28 00:00 [pmc-release]
AID - rmdopen-2017-000456 [pii]
AID - 10.1136/rmdopen-2017-000456 [doi]
PST - epublish
SO  - RMD Open. 2017 Jul 28;3(2):e000456. doi: 10.1136/rmdopen-2017-000456. eCollection 
      2017.