PPARγ Agonism Modulates Synovial Macrophage and Cartilage Responses in an Equine Model of Synovial Inflammation—Implications for Joint Therapy

Synovitis resolution is critical for joint homeostasis and prevents the progression of osteoarthritis (OA). Treatments like NSAIDs and intra-articular corticosteroids relieve symptoms by blocking pro-inflammatory mediators, but also impair the production of pro-resolving mediators, contributing to the likelihood of chronic synovitis. PPARγ signaling is an essential mechanism of synovitis resolution, which is decreased in OA tissues. To evaluate the potential of PPARγ agonists to promote pro-resolving pathways, equine macrophages cultured in autologous, normal, or inflamed synovial fluid (n = 10 horses) were treated with pioglitazone, geraniol, or both. Treatments modulated patterns of gene expression, increasing the expression of early drivers of resolution RELB and IL6, followed by increased NRF2 and PPARGC1A expression. Concentrations of TNF-α in conditioned synovial fluid significantly decreased as an early response to treatment, while IL10 concentrations also declined over time, suggesting increased tolerance to inflammatory stimuli and decreased compensatory feedback. Using an equine model of synovitis, intra-articular delivery of pioglitazone (n = 3 horses) or geraniol (n = 4 horses) was associated with decreased markers of synovium inflammation (geraniol) and enhanced cartilage proteoglycan preservation (geraniol and pioglitazone). In this small cohort of horses, no systemic or articular side effects were observed. Further studies optimizing treatment doses and regimens for intra-articular PPARγ agonism as a pro-resolving OA therapy are warranted.