Bone-Targeted Delivery of TGF-Beta Receptor Inhibitor as a Novel Treatment for Osteoarthritis
Abstract
Military personnel is highly susceptible to Osteoarthritis (OA). Both articular cartilage degeneration and subchondral bone malformation are primary concerns of OA. There is no effective disease-modifying treatment for OA except joint replacement surgery. Particularly, we are lacking fundamental treatment of OA pain although pain is the most prominent symptom of OA and the common reason that military personnel are discharged from service. The project aims to develop new therapies to attenuate OA degeneration and alleviate OA pain, thereby improving the quality of life of military soldiers. The structural and functional integrity of articular cartilage highly relies on its biochemical and biomechanical interplay with the subchondral bone. We have demonstrated that high levels of TGFbeta in subchondral bone initiates uncoupled subchondral bone formation and promote the degeneration of articular cartilage. Inhibition of TGFbeta signaling successfully improved the structure of subchondral bone and attenuated cartilage degeneration. However, TGFbeta is a well-known anabolic factor for articular cartilage and has a broad spectrum of functional activity on other organs/tissues throughout the body. The potential detrimental effect on other organs/tissues hinders the process of TGFbeta inhibitor being developed as an OA drug. To reach the purpose of both osteoclast inhibition and subchondral bone tissue-specific TGFbeta inhibition, we developed anew drug (ALN-LY conjugate) that links a TGFbeta inhibitor LY2109761 (LY) to an osteoclast inhibitor, Alendronate (ALN), through a metabolically hydrolyzable linker. We designed experiments to test 1): Whether ALN-LY conjugate can effectively rescue subchondral bone abnormalities and attenuate AC degeneration by specifically inhibiting TGFbeta signaling in bony tissue. 2): whether ALN-LY conjugate can alleviate OA symptom by suppressing subchondral bone turnover and consequent nociceptive innervation.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2021
- Accession Number
- AD1148593
Entities
People
- Gehua Zhen
Organizations
- Johns Hopkins University