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Senolytic Combination of Dasatinib and Quercetin Promotes Tendon-to-Bone Healing by Mitigating Age-Related Senescence
Zhuochang Cai1, Haoyuan Wang1, Jiacheng Hu1
1Department of Orthopedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Background:
An age-dependent increase in cellular senescence has been identified in rotator cuff tears (RCTs). The senolytic combination of dasatinib and quercetin (DQ) has been demonstrated to alleviate musculoskeletal diseases by mitigating age-related senescence. However, the effects of DQ treatment on tendon-to-bone healing remain unknown.
Purpose:
To investigate whether DQ treatment can enhance tendon-to-bone healing by reducing age-related senescence in an aged rat model.
Study Design:
Controlled laboratory study.
Methods:
First, 8 young adult (6-month-old) and 8 aged (24-month-old) rats with sham or RCT surgery were categorized into 4 groups: young sham, young RCT, aged sham, and aged RCT. Four weeks after surgery, the p21 expression of the supraspinatus-humerus complexes was evaluated. Next, 12 young adult and 24 aged rats with chronic RCT underwent repair surgery and were categorized into 3 groups: young (administered vehicle treatment), aged (administered vehicle treatment), and aged + DQ (administered DQ). Twelve weeks after repair, the gene expression and histological and biomechanical properties of the supraspinatus-humerus complexes were evaluated.
Results:
Aged rats demonstrated significantly higher p21 expression compared with young adult rats, and RCT surgery further enhanced p21 expression. The aged + DQ group demonstrated a significant decrease in the gene expression of senescence markers (p21 and p16) and senescence-associated secretory phenotype factors (IL-6, IL-1β, and MMP-3) compared with the aged group. Conversely, this group showed upregulation of both chondrogenic (Acan and Col2a1) and tenogenic (Col1a1, Tnmd, and Scx) genes. Histological analysis revealed that the aged + DQ group had decreased cellular senescence and improved cartilage and collagen development at the tendon-to-bone enthesis, with a higher histological score than the aged group. In addition, biomechanical testing indicated that the aged + DQ group had a higher failure load, stiffness, and stress than did the aged group.
Conclusion:
DQ treatment significantly alleviated age-related cellular senescence in the rotator cuff enthesis and enhanced tendon-to-bone healing in aged rats.
Clinical Relevance:
The senolytic combination of DQ could potentially provide effective clinical therapy for the treatment of RCT in older patients.
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