JAK Specific Signaling in PTOA-associated Joint Degeneration and Pain

Duke University, Durham NC

Investigators

Abstract

PROJECT SUMMARY Osteoarthritis (OA) is a total joint disease characterized by articular cartilage degradation, synovial inflammation, meniscus degeneration, subchondral bone sclerosis, osteophyte formation, and joint pain. It afflicts nearly 1/4 of the US population resulting in healthcare expenditures exceeding $185 billion annually. Despite the severity and impact of OA on individuals and our health care system, only recently have there been advances in understanding the molecular, cellular and tissue events underlying OA development and progression. It is well established that inappropriate expression and activation of catabolic enzymes underlies the joint cartilage destruction observed in OA, however the precise molecular mechanisms responsible for promoting joint cartilage catabolism is not well understood, nor is there a defined understanding of the molecular mediators of OA- associated pain. Recently, we determined that IL-6/JAK signaling is a critical mediator of both cartilage catabolism and pain in post-traumatic OA (PTOA) of male mice, and that particular JAK signaling molecules likely mediate PTOA-associated cartilage catabolism and pain. Here we will explore the relevant downstream mechanisms and test specific pharmacological inhibitors of these pathways as disease modifying osteoarthritis drugs (DMOADs). Using cartilage-specific and nociceptive neuron-specific inducible loss-of-function genetic approaches, we will identify the Janus Kinases (JAK1, JAK2, and/or TYK2) that mediate both/either the cartilage specific catabolic effects and the nociceptive pain responses associated with PTOA. A variety of in vivo and ex vivo approaches will identify the particular JAKs and critical downstream effectors as important regulators of PTOA-associated cartilage catabolism and pain, while simultaneously testing selective JAK inhibitors as potential translational DMOAD therapies.