Profibrotic mediators in tendon disease: a systematic review

Background: Tendon disease is characterized by the development of fibrosis. Transforming growth factor beta (TGF-beta), bone morphogenic proteins (BMPs) and connective tissue growth factor (CTGF) are key mediators in the pathogenesis of fibrotic disorders. The aim of this systematic review was to investigate the evidence for the expression of TGF-beta, BMPs and CTGF along tendon disease progression and the response of tendon cells to these growth factors accordingly. Method: We conducted a systematic screen of the scientific literature using the Medline database. The search terms used were tendon AND TGF-beta, tendon AND BMP or tendon AND CTGF. Studies of human samples, animal tendon injury and overuse models were included. Results: Thirty-three studies were included. In eight studies the expression of TGF-beta, BMPs or CTGF was dysregulated in chronic tendinopathy and tendon tear patient tissues in comparison with healthy control tissues. The expression of TGF-beta, BMPs and CTGF was increased and showed temporal changes in expression in tendon tissues from animal injury or overuse models compared with the healthy control (23 studies), but the pattern of upregulation was inconsistent between growth factors and also the type of animal model. No study investigated the differences in the effect of TGF-beta, BMPs or CTGF treatment between patient-derived cells from healthy and diseased tendon tissues. Tendon cells derived from animal models of tendon injury showed increased expression of extracellular matrix protein genes and increased cell signaling response to TGF-beta and BMP treatments compared with the control cells (two studies). Conclusion: The expression of TGF-beta, BMPs and CTGF in tendon tissues is altered temporally during healing in animal models of tendon injury or overuse, but the transition during the development of human tendon disease is currently unknown. Findings from this systematic review suggest a potential and compelling role for TGF-beta, BMPs and CTGF in tendon disease; however, there is a paucity of studies analyzing their expression and stimulated cellular response in well-phenotyped human samples. Future work should investigate the dynamic expression of these fibrotic growth factors and their interaction with tendon cells using patient samples at different stages of human tendon disease.