Bone-Targeted Delivery of TGF-Beta Receptor Inhibitor as a Novel Treatment for Osteoarthritis
Abstract
Osteoarthritis (OA) is the most common form of arthritis, affecting millions of people worldwide and causing a huge burden on society. It occurs when the protective cartilage on the ends of the bones (subchonral bone) wears down over time. Currently there is no effective pharmaceutical treatment for OA. Patients usually suffer with joint pain, stiffness, and limitation of movements for decades and eventually receive joint replacement surgery. It has been suggested that changes in the structure of the bone alter how it distributes the weight of the body on the cartilage and results in damage to the cartilage. Our group has previously identified that the abnormal increase of the level of growth factor TGFbeta is responsible for the sequential pathological changes in the osteoarthritic joint. Treatment with a specific TGFbeta inhibitor can prevent the damage to the subchondral bone and the cartilage. Unfortunately, TGFbeta is an important growth factor that plays critical roles in other organs throughout the body. TGFbeta also helps to maintain the healthy cartilage. Therefore, systemic inhibition of TGFbeta signaling could result in negative effects in other organs and compromise its beneficial effect in cartilage. We have synthesized a new drug (ALN-LY) in which the TGFbeta inhibitor is linked with alendronate using a chemical linker. Alendronate is bisphosphonate drug that has been widely used in clinics to treat osteoporosis. Because alendronate has high affinity to bony tissue, it can lead the TGFbeta inhibitor toward bony tissue upon uptake of the drug. The purpose of this study is to determine whether this new drug can effectively protect subchondral bone and cartilage damage in an OA mouse model. Moreover, joint pain is the major symptom of OA. However, long-term use of painkillers may have adverse effects and promote OA progression. We found that the activity of osteoclasts, a group of bone resorption cells, are responsible for the destruction of subchondral bone and joint pain. Both alendronate and TGFbeta inhibitor can prevent the destruction of subchondral bone and inhibit the production of osteoclasts. In the proposed study, we will also examine whether the ALN-LY can efficiently relieve joint pain using variety of behavior test methods for measuring pain behavior in mice. Since there is a lack of an effective drug on the market for OA, the success of the work described in this proposal will facilitate and accelerate therapeutic development of this disease and reduce the necessity of joint replacement surgery.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910222
Entities
People
- Gehua Zhen
Organizations
- Johns Hopkins University
- United States Army