Inflammation activation and resolution in human tendon disease

Abstract

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, NF-κB, glucocorticoid receptor and STAT-6. Inflammation signatures revealed expression of genes and proteins induced by Interferon and NF-κB in early stage disease and genes and proteins induced by STAT-6 and glucocorticoid receptor activation in advanced stage disease. The pro-resolving proteins FPR2/ALX and ChemR23 were increased in early stage disease compared to intermediate-advanced stage disease. Patients who were pain-free post-treatment had tendons with increased expression of CD206 and ALOX15 mRNA compared to tendons from patients who continued to experience pain post-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 Interferon target genes after treatment with lipopolysaccharide or IFNγ compared to stromal cells derived from healthy tendons. We identified 15-epi Lipoxin A 4 , a stable lipoxin metabolite derived from aspirin treatment, as potentially beneficial in the resolution of tendon inflammation. *Corresponding author Stephanie G Dakin, stephanie.dakin@ndorms.ox.ac.uk Corresponding author telephone +44 (0)1865 227374. Author contributions: SGD performed all experiments and wrote the manuscript with input from all co-authors. SGD, AJC and FOM designed the study. FOM, UO and GW provided qPCR reagents and FOM and UO performed array analysis. FOM and GW provided human macrophages for co-culture experiments. CY facilitated confocal image acquisition. BD, KW, BW, LR and AJC facilitated procurement and collection of healthy and diseased shoulder tendons from patients.

Tendon injury and repair – A perspective on the basic mechanisms of tendon disease and future clinical therapy

“…The matrix surrounding these cells is typically less well-structured, with inadequate hierarchical compartmentalization at the level of fascicles and above, and relatively disordered collagen structures at the level of fibers and below [192]. Additionally, the associated biochemical composition of the tissue may promote a chronic state of tissue inflammation, since among others pathological levels of collagen III with fewer cross links and increased presence of fragmented fibronectin are detected [191,[193][194][195][196][197][198][199]. At the levels of the tissue and organ, the effect of this aberrant tissue remodeling is an increased tendon crosssection that can provide adequate overall strength, but with suboptimal stiffness and function [8,[200][201][202][203].…”

Differential expression of alarmins—S100A9, IL-33, HMGB1 and HIF-1α in supraspinatus tendinopathy before and after treatment

“…8 However, there is growing support for the contribution of immune cells and inflammatory mediators to the development of tendinopathy. [9][10][11][12][13] Recent research showed that numbers of macrophages and mast cells are significantly increased in tendinopathic compared with healthy tendon tissues, and that inflammatory and fibrotic cytokines, peptides and growth factors have altered expression profiles in diseased compared with healthy tendons. 14 15 We recently reported that inflammatory signatures changed throughout different stages of severity in tissue samples from patients with supraspinatus tendinopathy.…”

High Concentration of Aspirin Induces Apoptosis in Rat Tendon Stem Cells via Inhibition of the Wnt/β-Catenin Pathway

“…Tendinopathy is one of the most common and most challenging problems for surgeons in orthopedics and sports medicine. Studies have reported that tendinopathy accounts for approximately 30% of sports injuries, and its pathogenesis is highly related to inflammation and degradation of connective tissue [14,15].…”