JSES - 2026-08-01 - Journal Article
Isotretinoin improves tendon-bone interface healing and inhibits muscle-fatty infiltration through GATA6 activation in a rat model of rotator cuff repair.
Yoon JP, Park SJ, Kim DH, Yoshida Y, Cho CH, Kim JY, Chung SW
Topics
Key Takeaway
Isotretinoin (7 mg/kg/day x 6 weeks) improved tendon-bone interface tensile strength and stiffness while reducing supraspinatus fatty infiltration in a rat rotator cuff repair model via GATA6-Caveolin-1-PKA/CREB signaling.
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Summary
This study tested whether oral isotretinoin enhances tendon-bone interface (TBI) healing and reduces fatty infiltration (FI) after rotator cuff repair in a rat transection model. Isotretinoin upregulated GATA6, downregulated Caveolin-1 and PPAR-γ, activated PKA/CREB phosphorylation, and produced superior Bonar histology scores, greater TBI tensile strength and stiffness, and markedly reduced supraspinatus FI compared to saline controls. The mechanistic axis identified is GATA6-Caveolin-1-PKA/CREB.
Key Limitation
The rat model uses a transection-and-immediate-repair construct that does not replicate the chronic degenerative tendon environment, fatty infiltration progression, or tissue quality seen in human rotator cuff tears, fundamentally limiting direct clinical translation.
Original Abstract
BACKGROUND
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.
PURPOSE
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.
METHODS
An RC repair rat model was established using 12-week-old male Sprague-Dawley rats. In the isotretinoin group, 10 rats received an oral dose of 7 mg/kg isotretinoin daily for 6 weeks following RC tendon transection, while the control group of 10 rats received only 0.9% saline. All rats were euthanized 6 weeks postsurgery. 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.
RESULTS
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.
CONCLUSIONS
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.