Inflammation activation and resolution in human tendon disease.
Improved understanding of the role of inflammation in tendon disease is required to facilitate therapeutic target discovery. We studied supraspinatus tendons from patients experiencing pain before and after surgical subacromial decompression treatment. Tendons were classified as having early, intermediate, or advanced disease, and inflammation was characterized through activation of pathways mediated by interferon (IFN), nuclear factor κB (NF-κB), glucocorticoid receptor, and signal transducer and activator of transcription 6 (STAT-6). Inflammation signatures revealed expression of genes and proteins induced by IFN and NF-κB in early-stage disease and genes and proteins induced by STAT-6 and glucocorticoid receptor activation in advanced-stage disease. The proresolving proteins FPR2/ALX and ChemR23 were increased in early-stage disease compared to intermediate- to advanced-stage disease. Patients who were pain-free after treatment had tendons with increased expression of CD206 and ALOX15 mRNA compared to tendons from patients who continued to experience pain after treatment, suggesting that these genes and their pathways may moderate tendon pain. Stromal cells from diseased tendons cultured in vitro showed increased expression of NF-κB and IFN target genes after treatment with lipopolysaccharide or IFNγ compared to stromal cells derived from healthy tendons. We identified 15-epi lipoxin A4, a stable lipoxin isoform derived from aspirin treatment, as potentially beneficial in the resolution of tendon inflammation.
Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Nuffield Orthopaedic Centre, Headington OX3 7LD, UK. NIHR Oxford Biomedical Research Unit, Botnar Research Centre, University of Oxford, Oxford OX3 7LD, UK.
Stephanie G
SG
Dakin
Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Nuffield Orthopaedic Centre, Headington OX3 7LD, UK.
Fernando O
FO
Martinez
Structural Genomics Consortium, University of Oxford, Old Road Campus, Headington OX3 7DQ, UK.
Clarence
C
Yapp
Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Nuffield Orthopaedic Centre, Headington OX3 7LD, UK.
Graham
G
Wells
Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Nuffield Orthopaedic Centre, Headington OX3 7LD, UK. Structural Genomics Consortium, University of Oxford, Old Road Campus, Headington OX3 7DQ, UK.
Udo
U
Oppermann
Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Nuffield Orthopaedic Centre, Headington OX3 7LD, UK. NIHR Oxford Biomedical Research Unit, Botnar Research Centre, University of Oxford, Oxford OX3 7LD, UK.
Benjamin J F
BJ
Dean
Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Nuffield Orthopaedic Centre, Headington OX3 7LD, UK. NIHR Oxford Biomedical Research Unit, Botnar Research Centre, University of Oxford, Oxford OX3 7LD, UK.
Richard D J
RD
Smith
Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Nuffield Orthopaedic Centre, Headington OX3 7LD, UK. NIHR Oxford Biomedical Research Unit, Botnar Research Centre, University of Oxford, Oxford OX3 7LD, UK.
Kim
K
Wheway
Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Nuffield Orthopaedic Centre, Headington OX3 7LD, UK. NIHR Oxford Biomedical Research Unit, Botnar Research Centre, University of Oxford, Oxford OX3 7LD, UK.
Bridget
B
Watkins
Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Nuffield Orthopaedic Centre, Headington OX3 7LD, UK. NIHR Oxford Biomedical Research Unit, Botnar Research Centre, University of Oxford, Oxford OX3 7LD, UK.
Lucy
L
Roche
Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Nuffield Orthopaedic Centre, Headington OX3 7LD, UK. NIHR Oxford Biomedical Research Unit, Botnar Research Centre, University of Oxford, Oxford OX3 7LD, UK.
Andrew J
AJ
Carr
D000293:Adolescent; D000328:Adult; D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism; D001241:Aspirin / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D007371:Interferon-gamma / Q000627:therapeutic use; D007372:Interferons / Q000378:metabolism; D037181:Lectins, C-Type / Q000378:metabolism; D008070:Lipopolysaccharides / Q000627:therapeutic use; D044045:Lipoxins / Q000378:metabolism; D008297:Male; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D019707:Receptors, Chemokine / Q000378:metabolism; D044042:Receptors, Formyl Peptide / Q000378:metabolism; D044067:Receptors, Lipoxin / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000378:metabolism; D052256:Tendinopathy / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013710:Tendons / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D055815:Young Adult
C102741:CMKLR1 protein, human; C105101:FPR2 protein, human; D037181:Lectins, C-Type; D008070:Lipopolysaccharides; D044045:Lipoxins; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D016328:NF-kappa B; D011956:Receptors, Cell Surface; D019707:Receptors, Chemokine; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; D050800:STAT6 Transcription Factor; C040527:lipoxin A4; D007371:Interferon-gamma; D007372:Interferons; C515716:ALOX15 protein, human; D001093:Arachidonate 15-Lipoxygenase; D001241:Aspirin