Small molecule stimulation of lubricin for treatment of post-traumatic osteoarthritis

Project Summary/Abstract The prevalence and cost of osteoarthritis is astounding, with total osteoarthritis-attributable medical expenditures and lost earnings surpassing $300 billion in 2013, accounting for more than 10% of healthcare costs. The lack of disease modifying drugs for osteoarthritis is a significant challenge as they could be particularly beneficial in post-traumatic osteoarthritis (PTOA). This project aims to address this challenge using a novel phenotypic reporter-based system to identify FDA approved drugs that stimulate lubricin production by human chondrocytes. This novel drug target, lubricin, has proved effective in viral delivery to the mouse joint, preventing osteoarthritis. The ability to increase lubricin expression pharmacologically would be of significant value. Primary human articular chondrocytes were genetically engineered into lubricin reporter cells using a lentiviral vector. We have confirmed chondrogenic activity and correlation of lubricin expression with Gaussia luciferase expression. These cells will be used to screen FDA approved drugs for anabolic effects promoting lubricin expression in a physiologically inspired 3D cartilage model after simulated injury. Hit compounds will be those that significantly increase expression. We will then further investigate lubricin stimulation with hit compounds both in vitro and in vivo. A non-invasive knee injury model will be used to create an anterior cruciate ligament tear. This tear is a common sports injury which, even with repair, results in osteoarthritis in ~50% of cases. Our studies will treat the mice with intra-articular injections to establish lubricin stimulation as a potential disease modifying approach. The expected outcome of this research is to establish anabolic therapies promoting lubricin expression as a cure/preventative treatment for post-traumatic osteoarthritis. Mechanistic studies, confirming or identifying novel targets of FDA approved drugs in stimulation of lubricin will be performed. Ultimately, lubricin stimulation through a pharmacological approach, will be shown to be an effective method to prevent post-traumatic osteoarthritis in both a human in vitro model and an in vivo mouse model.