Transcriptional and post-translational mechanisms of ECM remodeling in rotator cuff tendons under hyperlipidemic conditions

Rotator cuff injuries present significant clinical challenges, often resulting in chronic pain and functional impairment. In this study, we examined the effects of hyperlipidemia (HYP), a systemic metabolic condition, on tendon health. Histological analysis of infraspinatus tendons from hyperlipidemic swine revealed well-organized extracellular matrix (ECM) structures, comparable to those in non-hyperlipidemic (NONHYP) animals, suggesting ECM reorganization. Upstream SIGNOR3.0 analysis demonstrated that tumor necrosis factor receptor-associated factor 6 (TRAF6) activates transcription factor Yin Yang 1 (YY1) via kinase signaling, underscoring its role in tendon ECM remodeling. Hence, we futher examined the role of YY1, which is a critical regulator of collagen synthesis identified through network analysis. Although TRAF6 levels remained unchanged in HYP conditions, increased YY1 expression correlated with elevated COL1 gene expression. Additionally, twist-related protein 1 (TWIST1) emerged as another key molecule, existing in both homo- and heterodimer forms in NON-HYP conditions, but only as a heterodimer in HYP. YY1 enhanced COL1 transcription in the hyperlipidemic environment, while TWIST1 heterodimer formation facilitated collagen crosslinking. Notably, increased YY1 expression inhibited MMP3, resulting in the inactivity of MMP1, MMP8, and MMP9, thereby preserving collagen levels. These findings highlight the complex molecular interactions involving transcriptional regulation by YY1 and post-translational regulation by the TWIST1 heterodimer, essential for the deposition of mature collagen fibrils and driving tendon remodeling in hyperlipidemic conditions. This study offers valuable insights for the change of tendon health condition in hyperlipidemia disease or tendon pathology.