Injury or trauma to the knee, hip, or ankle is a well-documented contributor to premature onset of joint degeneration and osteoarthritis (OA). Nuclear factor kappa B (NF-?B) is a transcription factor that has early involvement in post-traumatic OA by activating genes involved in extracellular matrix catabolism and joint inflammation. Increased NF-?B activity has also been implicated in the development of pain following joint injury and other musculoskeletal pathologies. Despite the availability of numerous compounds that inhibit NF-?B, pharmacologic inhibition of NF-?B via systemic administration or even local delivery to the joint has not been successful in the treatment of OA. We hypothesize that intra-articular delivery of NF-?B antagonists from a safe, sustained-release carrier (silk) will have value in attenuating pain related sensitivities, joint dysfunction, and progressive joint pathology in a non-surgical, intra-articular fracture model of OA. We have previously identified a strong correlation between NF-?B activity and pain-related sensitivity in a model of inflammatory joint injury using the NF-?B-luciferase reporter mouse. Here, we will similarly track NF-?B activity, but in a mouse model of closed tibial fracture as a non-surgical model of joint injury which is known to progress to OA.
In Specific Aim 1, we will evaluate the temporal and spatial development of NF-?B activity, pain- related sensitivities, and joint dysfunction in mice following intra-articular fracture out to 8 weeks. We will identify relationships between systemic and local NF-?B activation, patterns for sensitivity, gait and weight- bearing, and arthritis progression following joint fracture. Results will identify ?therapeutic windows? for timing of intra-articular drug delivery in Specific Aim 3.
In Specific Aim 2, we will optimize silk fibroin microparticle depots for sustained release of two small molecule NF-?B inhibitors, SC-514 or PHA-408. We have previously demonstrated increased residence times for silk fibroin microparticles when delivered to the joint space, but have not incorporated a drug for sustained release. Silk fibroin microparticles (10-60 microns) will be fabricated specific to each NF-?B inhibitor, and tested to verify high drug loading and sustained release out to 4 weeks.
In Specific Aim 3, we will evaluate if a single, intra-articular injection of SC-514 or PHA-408-loaded silk fibroin microparticles can attenuate NF-?B activation, pain-related sensitivities, joint dysfunction, and joint pathology after intra-articular fracture. Intra-articular injections of drug-loaded microparticles will be administered to the injured limb at either early or late times after injury, with longitudinal monitoring of effects on NF-?B activation, pain-related sensitivities, joint dysfunction and arthritis development. Results will reveal whether either compound, and at which time, can modulate defined outcome measures of arthritis symptoms and/or pathology progression in this model of OA. This work will establish a safe, sustained release strategy for the local treatment of OA that can advance utility for an entire class of small molecule NF-?B antagonists with a high likelihood for treating pathology and/or pain development in patients with OA.

Public Health Relevance

This study will develop a safe, sustained-release drug depot from silk, formulated specifically for small molecule antagonists of inflammation to be injected into the joint space. This work will establish a new strategy for the treatment of osteoarthritis that has potential to improve clinical utility for an entire class of inexpensive small molecule drugs that has a high likelihood of treating pathology or pain development in patients affected by osteoarthritis.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Musculoskeletal Tissue Engineering Study Section (MTE)
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Kirilusha, Anthony G
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Washington University
Biomedical Engineering
Biomed Engr/Col Engr/Engr Sta
Saint Louis
United States
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