PMID- 27452303
OWN - NLM
STAT- MEDLINE
DCOM- 20180102
LR  - 20181113
IS  - 1469-445X (Electronic)
IS  - 0958-0670 (Print)
IS  - 0958-0670 (Linking)
VI  - 101
IP  - 10
DP  - 2016 Oct 1
TI  - OPN-a induces muscle inflammation by increasing recruitment and activation of 
      pro-inflammatory macrophages.
PG  - 1285-1300
LID - 10.1113/EP085768 [doi]
AB  - What is the central question of this study? What is the functional relevance of 
      OPN isoform expression in muscle pathology? What is the main finding and its 
      importance? The full-length human OPN-a isoform is the most pro-inflammatory 
      isoform in the muscle microenvironment, acting on macrophages and myoblasts in an 
      RGD-integrin-dependent manner. OPN-a upregulates expression of tenascin-C (TNC), 
      a known Toll-like receptor 4 (TLR4) agonist. Blocking TLR4 signalling inhibits 
      the pro-inflammatory effects of OPN-a, suggesting that a potential mechanism of 
      OPN action is by promoting TNC-TLR4 signalling. Although osteopontin (OPN) is an 
      important mediator of muscle remodelling in health and disease, functional 
      differences in human spliced OPN variants in the muscle microenvironment have not 
      been characterized. We thus sought to define the pro-inflammatory activities of 
      human OPN isoforms (OPN-a, OPN-b and OPN-c) on cells present in regenerating 
      muscle. OPN transcripts were quantified in normal and dystrophic human and dog 
      muscle. Human macrophages and myoblasts were stimulated with recombinant human 
      OPN protein isoforms, and cytokine mRNA and protein induction was assayed. OPN 
      isoforms were greatly increased in dystrophic human (OPN-a > OPN-b > OPN-c) and 
      dog muscle (OPN-a = OPN-c). In healthy human muscle, mechanical loading also 
      upregulated OPN-a expression (eightfold; P < 0.01), but did not significantly 
      upregulate OPN-c expression (twofold; P > 0.05). In vitro, OPN-a displayed the 
      most pronounced pro-inflammatory activity among isoforms, acting on both 
      macrophages and myoblasts. In vitro and in vivo data revealed that OPN-a 
      upregulated tenascin-C (TNC), a known Toll-like receptor 4 (TLR4) agonist. 
      Inhibition of TLR4 signalling attenuated OPN-mediated macrophage cytokine 
      production. In summary, OPN-a is the most abundant and functionally active human 
      spliced isoform in the skeletal muscle microenvironment. Here, OPN-a promotes 
      pro-inflammatory signalling in both macrophages and myoblasts, possibly through 
      induction of TNC-TLR4 signalling. Together, our findings suggest that specific 
      targeting of OPN-a and/or TNC signalling in the damaged muscle microenvironment 
      may be of therapeutic relevance.
CI  - (c) 2016 The Authors. Experimental Physiology published by John Wiley & Sons Ltd on 
      behalf of The Physiological Society.
FAU - Many, Gina M
AU  - Many GM
AD  - Research Center for Genetic Medicine, Children's National Medical Center, 
      Washington, DC, USA.
AD  - Department of Integrative Systems Biology, George Washington University School of 
      Medicine & Health Sciences, Washington, DC, USA.
AD  - Department of Cell, Developmental and Integrative Biology, University of Alabama 
      Birmingham, Birmingham, AL, USA.
FAU - Yokosaki, Yasuyuki
AU  - Yokosaki Y
AD  - Hiroshima University, Minamiku, Hiroshima, Japan.
FAU - Uaesoontrachoon, Kitipong
AU  - Uaesoontrachoon K
AD  - Research Center for Genetic Medicine, Children's National Medical Center, 
      Washington, DC, USA.
FAU - Nghiem, Peter P
AU  - Nghiem PP
AD  - Research Center for Genetic Medicine, Children's National Medical Center, 
      Washington, DC, USA.
AD  - Department of Integrative Systems Biology, George Washington University School of 
      Medicine & Health Sciences, Washington, DC, USA.
AD  - Department of Veterinary Integrative Biosciences, Texas A&M University, College 
      Station, TX, USA.
FAU - Bello, Luca
AU  - Bello L
AD  - Research Center for Genetic Medicine, Children's National Medical Center, 
      Washington, DC, USA.
FAU - Dadgar, Sherry
AU  - Dadgar S
AD  - Research Center for Genetic Medicine, Children's National Medical Center, 
      Washington, DC, USA.
FAU - Yin, Ying
AU  - Yin Y
AD  - National Institute of Dental and Craniofacial Research, National Institutes of 
      Health, Bethesda, MD, USA.
FAU - Damsker, Jesse M
AU  - Damsker JM
AD  - Research Center for Genetic Medicine, Children's National Medical Center, 
      Washington, DC, USA.
AD  - ReveraGen BioPharma, Rockville, MD, USA.
FAU - Cohen, Heather B
AU  - Cohen HB
AD  - Department of Cell Biology and Molecular Genetics, University of Maryland, 
      College Park, MD, USA.
FAU - Kornegay, Joe N
AU  - Kornegay JN
AD  - Department of Veterinary Integrative Biosciences, Texas A&M University, College 
      Station, TX, USA.
FAU - Bamman, Marcas M
AU  - Bamman MM
AD  - Department of Cell, Developmental and Integrative Biology, University of Alabama 
      Birmingham, Birmingham, AL, USA.
FAU - Mosser, David M
AU  - Mosser DM
AD  - Department of Cell Biology and Molecular Genetics, University of Maryland, 
      College Park, MD, USA.
FAU - Nagaraju, Kanneboyina
AU  - Nagaraju K
AD  - Research Center for Genetic Medicine, Children's National Medical Center, 
      Washington, DC, USA.
AD  - Department of Integrative Systems Biology, George Washington University School of 
      Medicine & Health Sciences, Washington, DC, USA.
FAU - Hoffman, Eric P
AU  - Hoffman EP
AD  - Research Center for Genetic Medicine, Children's National Medical Center, 
      Washington, DC, USA. ehoffman@binghamton.edu.
AD  - Department of Integrative Systems Biology, George Washington University School of 
      Medicine & Health Sciences, Washington, DC, USA. ehoffman@binghamton.edu.
LA  - eng
GR  - P50 AR060836/AR/NIAMS NIH HHS/United States
GR  - R01 NS029525/NS/NINDS NIH HHS/United States
GR  - K26 OD011171/OD/NIH HHS/United States
GR  - P50 AR060836/AR/NIAMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20160924
PL  - England
TA  - Exp Physiol
JT  - Experimental physiology
JID - 9002940
RN  - 0 (Cytokines)
RN  - 0 (Protein Isoforms)
RN  - 0 (RNA, Messenger)
RN  - 0 (Toll-Like Receptor 4)
RN  - 106441-73-0 (Osteopontin)
SB  - IM
MH  - Adult
MH  - Animals
MH  - Cells, Cultured
MH  - Cytokines/metabolism
MH  - Dogs
MH  - Female
MH  - Humans
MH  - Inflammation/*metabolism
MH  - Macrophages/*metabolism
MH  - Male
MH  - Mice
MH  - Middle Aged
MH  - Muscle, Skeletal/*metabolism
MH  - Myoblasts/metabolism
MH  - Osteopontin/*metabolism
MH  - Protein Isoforms/metabolism
MH  - RNA, Messenger/metabolism
MH  - Signal Transduction/physiology
MH  - Toll-Like Receptor 4/metabolism
MH  - Up-Regulation/physiology
PMC - PMC5095808
OTO - NOTNLM
OT  - Duchenne muscular dystrophy
OT  - OPN-a
OT  - TNC
OT  - muscle inflammation
OT  - osteopontin
OT  - skeletal muscle
EDAT- 2016/07/28 06:00
MHDA- 2018/01/03 06:00
PMCR- 2016/11/04
CRDT- 2016/07/26 06:00
PHST- 2016/02/25 00:00 [received]
PHST- 2016/07/15 00:00 [accepted]
PHST- 2016/07/28 06:00 [pubmed]
PHST- 2018/01/03 06:00 [medline]
PHST- 2016/07/26 06:00 [entrez]
PHST- 2016/11/04 00:00 [pmc-release]
AID - EPH1854 [pii]
AID - 10.1113/EP085768 [doi]
PST - ppublish
SO  - Exp Physiol. 2016 Oct 1;101(10):1285-1300. doi: 10.1113/EP085768. Epub 2016 Sep 
      24.