Xanthohumol suppresses ECM degradation in osteoarthritis through the Nrf2/PERK/ATF4/C/EBPβ signaling pathway

In this study, the therapeutic efficacy of Xanthohumol (XH) was evaluated as a preventive agent for extracellular matrix (ECM) degradation in osteoarthritis, using the in vivo monosodium iodoacetate-induced arthritis model in rats, along with the in vitro model of interleukin (IL)-1β-stimulated C28/I2 chondrocytes. With established concentrations of XH, the extent to which this compound may modulate cartilaginous architecture, enzymatic activity, or ECM synthesis was determined. The results clearly show that, in comparison with controls, this drug significantly reduced the catabolism of ECM, exerting a concentration-dependent effect that reduced the production of MMP13 (by 46% in vitro) with enhanced transcriptional production of collagen II (by 38% in vitro) versus controls, as well as exhibiting a cartilage degradation reduction of 31% compared with controls. The results, based on downstream messenger studies, show that this drug reduced transcriptional activation of ER-stress-driven catabolism associated with the PERK/ATF4/C/CEBPβ pathway, with a subsequent, noteworthy increase (by 52%) in the transcriptional activity of Nrf2. Over-expression or activation studies reduced the chondroprotective effects, entirely eliminating the silencing studies of Nrf2. These results clearly indicate that this drug, with its chondroprotective effects, suppresses catabolism, stimulates cartilaginous reinstatement, and reversibly decreases OARSI scores in treated animals. This study indicates that this drug may offer a promising therapeutic modality in modulating ER-stress-driven catabolysis as its pathomechanistic principle in targeted use for osteoarthritis prevention.