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 injuries are a common age-related degenerative condition where current treatment strategies fail to restore functionality and normal quality of life. This disease also occurs naturally in horses, with many similarities to human tendinopathy making it an ideal large animal model for human disease. Regenerative approaches are increasingly used to improve outcome involving mesenchymal stem cells (MSCs), supported by clinical data where injection of autologous bone marrow derived MSCs (BM-MSCs) suspended in marrow supernatant into injured tendons has halved the re-injury rate in racehorses. We hypothesized that stem cell therapy induces a matrix more closely resembling normal tendon than the fibrous scar tissue formed by natural repair. Twelve horses with career-ending naturally-occurring superficial digital flexor tendon injury were allocated randomly to treatment and control groups. 1X107 autologous BM-MSCs suspended in 2 ml of marrow supernatant were implanted into the damaged tendon of the treated group. The control group received the same volume of saline. Following a 6 month exercise programme horses were euthanized and tendons assessed for structural stiffness by non-destructive mechanical testing and for morphological and molecular composition.BM-MSC treated tendons exhibited statistically significant improvements in key parameters compared to saline-injected control tendons towards that of normal tendons and those in the contralateral limbs. Specifically, treated tendons had lower structural stiffness (p<0.05) although no significant difference in calculated modulus of elasticity, lower (improved) histological scoring of organisation (p<0.003) and crimp pattern (p<0.05), lower cellularity (p<0.007), DNA content (p<0.05), vascularity (p<0.03), water content (p<0.05), GAG content (p<0.05), and MMP-13 activity (p<0.02).Treatment with autologous MSCs in marrow supernatant therefore provides significant benefits compared to untreated tendon repair in enhancing normalisation of biomechanical, morphological, and compositional parameters. These data in natural disease, with no adverse findings, support the use of this treatment for human tendon injuries.
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