The protective role of CD44 and microRNA-146a in tendinopathy.

AIMS: Tendinopathy is a pathological condition characterized by pain and significant dysfunction, with its pathogenesis involving various factors including chronic inflammation, cellular senescence, and apoptosis. Previous research indicates that blocking CD44 signalling exacerbates apoptosis and inflammation in tendinopathic tenocytes. Furthermore, microRNA-146a (miR-146a) has been shown to counteract interleukin-1β (IL)-1β-induced senescence in these cells, and is upregulated by CD44 in knee osteoarthritis. Therefore, this study aimed to investigate the CD44-miR-146a signalling axis in regulating apoptosis in tendinopathy. METHODS: Lentiviral vectors (LVs) were used to overexpress CD44 cDNA (LVCD44) and miR-146a precursor (LVmiR-146a) in rat primary tendinopathic tenocytes and tendons. Apoptosis was assessed using terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) staining. To dissect the CD44-AKT-miR-146a signalling pathway, the PI3K/AKT inhibitor LY294002 and the CD44 antagonizing antibody OX-50 were used. In situ hybridization (ISH) and immunohistochemistry (IHC) were performed to examine the pathway's effect on Smad4 expression in tendinopathic tenocytes and tendons. RESULTS: Overexpression of CD44 and miR-146a in tendinopathic tenocytes resulted in significantly reduced apoptosis compared to controls. The CD44-AKT-miR-146a signalling axis was found to mitigate apoptosis in IL-1β-stimulated tenocytes and in a rat model of collagenase-induced Achilles tendinopathy, primarily by suppressing Smad4 expression. CONCLUSION: This study highlights the protective role of the CD44-AKT-miR-146a axis in tendinopathy. By modulating the AKT/miR-146a/Smad4 signalling pathway, CD44 and miR-146a effectively reduce apoptosis in tendinopathic tenocytes and tendons.