Rapamycin insensitive regulation of engineered ligament structure and function by IGF-1

Area of Science:

• Biomaterials Science
• Tissue Engineering
• Orthopedic Surgery

Background:

• Anterior cruciate ligament (ACL) rupture necessitates surgical repair due to poor natural healing.
• Engineered ligament grafts currently lack sufficient strength for clinical use.
• Insulin-like growth factor-1 (IGF-1) shows promise in improving engineered ligament properties.

Purpose of the Study:

• To investigate the role of the mTORC1 pathway in IGF-1-mediated improvements in engineered human ligaments.
• To determine if IGF-1's effects on collagen content and mechanical properties are dependent on mTORC1 activity.
• To elucidate the mechanisms by which IGF-1 enhances engineered ligament quality.

Main Methods:

• Engineered human ligaments were treated with IGF-1 and/or rapamycin (an mTORC1 inhibitor).
• Mechanical properties (strength, stiffness) and collagen content were assessed after treatment.
• Procollagen synthesis and collagen degradation rates were quantified.

Main Results:

• IGF-1 significantly increased mechanical properties (34%) and collagen content (63%).
• Rapamycin decreased mechanical properties (-24.5%) and collagen content (-36%).
• IGF-1 decreased collagen degradation (15%) independently of rapamycin, while rapamycin blocked IGF-1's effect on collagen synthesis.

Conclusions:

• IGF-1 enhances engineered ligament mechanics and collagen content primarily by reducing collagen degradation via an mTORC1-independent pathway.
• While IGF-1's anticatabolic effects are mTORC1-independent, its anabolic effects on collagen synthesis are blocked by rapamycin.
• These findings suggest a complex interplay between IGF-1, mTORC1, and collagen metabolism that may impact ACL graft healing and rehabilitation.