Isotretinoin improves tendon-bone interface healing and inhibits muscle-fatty infiltration through GATA6 activation in a rat model of rotator cuff repair.

Abstract

Rotator cuff (RC) repair often fails due to poor healing at the tendon-to-bone interface (TBI) and irreversible fatty infiltration (FI) of the muscle. GATA6 has emerged as a potential transcriptional regulator of tissue regeneration, but no therapeutic agents currently target this pathway. To evaluate the therapeutic potential of isotretinoin, a known GATA6 modulator, in enhancing TBI healing and reducing FI following RC repair in a rat model. Level Ⅴ, Controlled laboratory study. An RC repair rat model was established using 12-week-old male Sprague-Dawley rats. In the isotretinoin group, ten rats received an oral dose of 7 mg/kg isotretinoin daily for six weeks following RC tendon transection, while the control group of ten rats received only 0.9% saline. All rats were euthanized six weeks post-surgery. FI in the supraspinatus tendon was assessed qualitatively and quantitatively. TBI healing was histologically evaluated using the Bonar score after general tissue staining. Additionally, a biomechanical assessment of TBI healing was conducted utilizing a universal testing machine. Isotretinoin treatment significantly upregulated Gata6 expression while downregulating Caveolin-1 and PPAR-γ, with no significant change in C/EBP-α expression. Activation of the PKA/CREB signaling pathway was confirmed by increased phosphorylation of PKA and CREB. Histological analysis demonstrated improved collagen organization and cellularity at the TBI. Biomechanical testing revealed greater tensile strength and stiffness in the isotretinoin group compared to controls. Fatty infiltration in the supraspinatus muscle was markedly reduced. Isotretinoin promotes TBI healing and suppresses muscle-FI following RC repair, which is associated with activation of the GATA6-Caveolin-1-PKA/CREB signaling axis. This study identifies isotretinoin as a promising pharmacologic strategy to enhance RC repair outcomes by targeting a novel molecular axis. Drug repurposing of isotretinoin may offer a translatable solution for reducing RC repair failure in clinical settings.