TGF-ò rescues extracellular matrix turnover in rotator cuff pathology

Abstract

Introduction: Tendinopathies are the most frequent causes of chronic shoulder pain. Long head of the biceps (LHB) tendon lesions are often associated with massive rotator cuff (RC) tears. Palliative LHB tenotomy decreases RC disease patient’s pain and disability. The aim of this work was to identify the biological changes of LHB in RC disease and assess its association with clinical manifestations. Methods: RC disease patients submitted to LHB tenotomy were evaluated using a clinical protocol in order to retrieve information regarding shoulder pain duration and intensity (visual analogue scale) and shoulder function (Constant score). LHB tendon samples from these patients were compared with cadaver controls. Tendon tissue was qualitatively studied by conventional histology and immunohistochemistry was used to access semi quantitatively the presence of substance P and calcitonin gene-related peptide (CGRP). Tendon cell cultures were used to determine the gene expression of several extracellular matrix genes with and without stimulation with transforming growth factor (TGF)-β, TNF, IL-10 or dexamethasone. Results: Histologically, LHB tendon from RC patients and cadaver controls had similar characteristics. RC patients had a significantly higher CGRP immunohistochemistry score as compared to controls (p=0.010) but there was no correlation with patient clinical features. On the contrary, regarding substance P no differences were found between RC patients and controls immunohistochemistry score but a correlation with shoulder pain (r=0.828, p=0.021) was identified. Through gene expression analysis we found a downregulation of the extracellular matrix genes type I collagen and thrombospondin 4, as well as vascular endothelial growth factor (VEGF) and nerve growth factor (NGF) in Manuscript Click here to download Manuscript manuscript.docx 2 patients with RC disease. However, in vitro stimulation of RC tenocytes with TGF-β rescued their ability to produce type I collagen and VEGF. Conclusion: LHB tendon from RC disease patients had neurotransmitter disturbances that could be related to shoulder pain. Moreover, we demonstrated that LHB from RC disease patients had a downregulation of extracellular matrix genes, as well as of VEGF and NGF genes. We showed that TGF-β can partially normalize the expression of these genes, suggesting that modulating TGF-β could be a therapeutic opportunity for improving tendon quality in the context of chronic tendinopathies.