Pharmacological Inhibition of STING with H-151 Promotes Rotator Cuff Healing in Aged Rats
Zhuochang Cai, Cheng Qu, Jiacheng Hu, Zhenyu Chen, Jian Lu, Wei Wang, Tengfei Lou, Cunyi FanBackground:
Although the cGAS-STING (cyclic GMP-AMP synthase-stimulator of interferon genes) pathway is a key driver of inflammaging in age-related musculoskeletal disorders, its role in age-related rotator cuff tears (RCTs) remains unknown. This study investigated whether inhibition of the cGAS-STING pathway with H-151 could improve tendon-to-bone healing in aged rats after rotator cuff repair (RCR).
Methods:
Forty-eight Sprague-Dawley rats were assigned to 4 groups: young control (sham surgery), aged control (sham surgery), aged RCT (RCR with fibrin), and aged RCT+H-151 (RCR with H-151-loaded fibrin). Rats in the RCT groups underwent bilateral RCR, after which the tendon-bone enthesis was treated with the respective fibrin gel. The status of the cGAS-STING pathway, expression of inflammaging and differentiation markers, and histological and biomechanical properties of the supraspinatus-humerus complex were evaluated.
Results:
The cGAS-STING pathway was markedly activated at the tendon-bone enthesis in the aged rats. Treatment with H-151 effectively suppressed its downstream effectors (
Conclusions:
The cGAS-STING pathway was activated at the tendon-bone enthesis in aged rats. The inhibition of STING with H-151 in similar rats attenuated inflammaging, promoted collagen maturation and fibrocartilage regeneration, and substantially improved the biomechanical properties of the repaired enthesis.
Clinical Relevance:
Inhibition of the cGAS-STING pathway using STING antagonists may be a promising therapeutic strategy for enhancing rotator cuff healing in older patients.