Temporal Gene Expression Changes in Rotator Cuff Tendon Injury and Repair.

Abstract

Rotator cuff tendon injuries are common, particularly among the elderly. However, promising biomarkers to assess tendon degeneration and healing remain limited. This study aimed to identify dynamic biomarkers by analyzing temporal gene expression and histological changes in a chronic rotator cuff tear model. Using Sprague-Dawley rats, a chronic injury was induced by detaching the supraspinatus tendon and inserting a silastic drain to inhibit spontaneous healing. Tendon samples were collected at multiple time points after injury and after repair for gene expression profiling and histological analysis. Human supraspinatus tendon samples (normal and degenerative) were acquired for validation. A three-dimensional in vitro tendon construct model using human adipose-derived stem cells was subjected to mechanical loading to investigate gene expression under controlled conditions. Tendon-specific markers, including Scleraxis, Tenascin C, and Collagen III, were downregulated early after injury but demonstrated partial recovery with scar formation, limiting their utility as healing indicators. Conversely, Collagen I and YAP1 showed significant downregulation during progressive tendon degeneration and marked upregulation following surgical repair. Histological improvements in collagen organization corresponded with YAP1 re-expression during the recovery phase. YAP1 was consistently reduced in human degenerative tendons. In vitro, mechanical loading enhanced the nuclear localization of YAP1 and upregulated tendon-specific gene expression, confirming its mechanosensitivity. These findings establish YAP1 as a mechanotransducer and a promising biomarker of tendon degeneration and regeneration, with potential therapeutic relevance. This study demonstrated the translational value of YAP1 by integrating animal, human, and in vitro models to identify a robust marker of tendon remodeling.