Tendinopathy is a common global disease burden, causing pain and disability. These injuries require prolonged convalescence and there are currently no effective treatments. In the study by Dakin et al. the authors investigated why tendon inflammation fails to resolve in some patients with chronic disease. They studied profiles of pro-inflammatory and inflammation resolving lipids in tendon stromal fibroblasts isolated from patients with tendinopathy and compared them with those derived from healthy donors. Cells from patients with tendinopathy displayed a pro-inflammatory profile and dysregulated resolution responses compared to cells isolated from healthy volunteers. Incubating tendon stromal cells in tissue protective pro-resolving compounds including the aspirin stable isoform 15-epi-LXA4 induced the production of other proresolving lipid mediators and moderated the pro-inflammatory phenotype of diseased tendon stromal cells.
The investigators noted that the effects of 15-epi-LXA4 treatment were more profound in healthy compared to diseased tendon stromal cells. They identified that cells from tendinopathy patients displayed enhanced ability to convert proresolving mediators to metabolites that carry reduced biological actions. Diseased tendon tissues and cells highly expressed an enzyme (15-PGDH) implicated in the inactivation of tissue protective proresolving mediators. Inhibition of 15-PGDH significantly reduced the further conversion of proresolving mediators and moderated the inflammatory phenotype of diseased tendon cells. These findings suggest that chronic inflammation in musculoskeletal soft tissues may result from dysregulated resolution responses. The authors propose that a dual pronged approach, using pro-resolving mediators together with inhibitors to 15-PGDH represents a novel therapeutic strategy to reduce local tendon inflammation and promote tissue repair.
Spectra identifying the further metabolites of pro-resolving mediators in tendon stromal cells isolated from healthy volunteers (HV) and patients with tendon disease (TD). Cells from tendinopathy patients displayed enhanced ability to convert tissue protective proresolving mediators to metabolites that carry reduced biological actions. Staining shows cells from patients with tendinopathy highly express 15-PGDH, implicated in the inactivation of proresolving mediators.
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Increased 15-PGDH expression leads to dysregulated resolution responses in stromal cells from patients with chronic tendinopathy. Stephanie G Dakin, Lucy Ly, Romain A. Colas, Udo Oppermann, Kim Wheway, Bridget Watkins, Jesmond Dalli, Andrew J Carr.