PB125 modifies histopathology, redox homeostasis, and mobility in a sex-specific manner in Hartley guinea pigs

The pathogenesis of primary osteoarthritis (OA) is complex, multifactorial, and largely undetermined. Nuclear factor-erythroid 2-related factor-2 (Nrf2) is a transcription factor that regulates hundreds of genes involved with cytoprotection. The role of the Nrf2 pathway in early OA remains relatively undefined. We utilized the Hartley guinea pig model of idiopathic OA to investigate the utility of a purported Nrf2 activator, PB125, in delaying the onset of knee OA. We hypothesized that three months of daily PB125 supplementation would modify structural, molecular, and in vivo functional outcomes characteristic of OA. Fifty-six 2-month-old Hartley guinea pigs (sexes equally represented) were treated orally with PB125 or volume equivalent vehicle control for 3 months; animals were sacrificed at 5 months, an age representing mild OA changes and early disease in control animals. Outcome measures included: knee histopathology, mRNA expression, immunohistochemistry, and in vivo mobility outcomes. There were sex differences in OA outcomes and mRNA expression independent of treatment. Correspondingly, PB125 treatment had differing effects in males and females. Male PB125 treated animals had lower patella OA scores and modified voluntary mobility patterns. In contrast, female PB125 treated animals had differential gene and protein expression patterns in articular cartilage in markers related to redox homeostasis and subsequent increases in compulsory mobility metrics. In summary, PB125 may modify molecular mechanisms involved in the initiation of early OA in a sex-dependent fashion. Conclusions/Clinical Significance: Collectively, this work serves as rationale for future investigations into the utility of PB125 in delaying the onset of OA.