PPAR- Activation in the Treatment of Joint Inflammation

Abstract Osteoarthritis (OA) is the most prevalent equine joint disease accounting for approximately 60% of lameness cases in horses. In addition to causing significant morbidity, the financial impact of OA to the equine industry is estimated at around $300 million per year, largely due to veterinary care and the early retirement of horses. Synovitis is a central feature of OA and is primarily driven by synovial macrophages. While macrophages drive acute stages of inflammation, they also coordinate its natural resolution, an important process that requires a fine balance of pro- and anti-inflammatory mechanisms that are essential to counteract damage, repair tissues, and recover joint health. To uncover mechanisms by which BMNC induce resolution of synovitis, we profiled the transcriptome and secretome of BMNC in response to joint inflammation. BMNC mediates resolution through a short pro-inflammatory response that triggers the production of many drivers of resolution. This effect is largely achieved by multiple mechanisms that collectively enhance activation of the peroxisome proliferator-activated receptor gamma (PPAR-γ). Activation of PPAR-γ modulates mitochondrial metabolism, enhancing the resistance of macrophages to inflammatory oxidative stress and their production of pro-resolving and reparative factors (e.g. IL-10, IGF-1). Following on the exciting findings from our previous GJCRF study "Bone marrow mononuclear cells for equine joint therapy", therapeutic activation of PPAR-γ signaling provides a unique opportunity to treat joint inflammation while avoiding the negative side-effects from several of the widely-used anti-inflammatory drugs. This study will first focus on three PPAR-γ agonists, to identify which of them generate a pro-resolving response in macrophages that closely resembles that of BMNC (4). Further, the in vivo effect of such molecule will be assessed in experimentally inflamed equine joints, as a candidate treatment for joint inflammation.