Caffeic acid phenethyl ester attenuates osteoarthritis progression by activating NRF2/HO‑1 and inhibiting the NF‑κB signaling pathway

Abstract

Osteoarthritis (OA) is the most common degenerative disease affecting the joints, and inflammation appears to play a critical role in the initiation and progression of OA. Caffeic acid phenethyl ester (CAPE), a natural flavonoid compound, has anti-inflammatory and antioxidant functions. However, its anti-inflammatory effects on OA and the underlying mechanisms of action of CAPE in the treatment of OA remain elusive. Therefore, the present study investigated the anti-inflammatory effects of CAPE on IL-1β-stimulated chondrocytes in vitro and surgically induced rat models of OA in vivo. In vitro, CAPE reduced the expression of inducible nitric oxide synthase and cyclooxygenase-2 in IL-1β-stimulated chondrocytes, as well as the extracellular secretion of nitric oxide and prostaglandin E2 in the cell culture supernatants. In addition, CAPE attenuated the degradation of extracellular matrix by increasing the expression of aggrecan and collagen II, and decreasing the expression of MMP3, MMP13 and a disintegrin and metalloproteinase with thrombospondin motif-5. Furthermore, CAPE attenuated NF-κB signaling and activated the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 signaling pathway in IL-1β-stimulated chondrocytes. In vivo, CAPE protected cartilage from destruction and delayed the progression of OA in rats. Taken together, the findings of the present study indicated that CAPE may be a potential therapeutic agent for the prevention or treatment of OA.

Overview of Anti-Inflammatory and Anti-Nociceptive Effects of Polyphenols to Halt Osteoarthritis: From Preclinical Studies to New Clinical Insights

“…Several authors have investigated in vitro the effect of PPs on inflammation in OA [ 25 , 26 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 ,...…”

“…As for the other PPs, they act similarly to those above-mentioned in inhibiting inflammation. In particular, several other PPs inhibit NFkB signaling: i.e., carnosol [ 118 ], CAPE [ 119 ], tangeretin [ 120 ], nobiletin [ 121 ], naringenin [ 122 ], theaflavin-3-3′-digallate [ 123 ], cyanidin [ 124 , 125 ], ellagic acid [ 126 ]. Similarly to resveratrol and quercetin, other PPs modulate epigenome by acting as SIRT1 inductors: i.e., ferulic acid [ 127 ], fisetin [ 128 ], procyanidins [ 129 ]; while cyanidin was showed to increase SIRT6 [ 125 ].…”

“…Moreover, one of the most documented pathways up-regulated by PPs is the NRF2/HO1; i.e., sinapic acid [ 136 , 137 ], xanthohumol [ 138 ], myricetin [ 139 ], lutein [ 140 ], theaflavin-3-3′-digallate [ 123 ], delphinidin [ 141 ], 6-gingerol [ 26 ], CAPE [ 119 ], genistein [ 25 ] and tangeretin [ 120 ]. In particular, it has been reported that Nrf2 and HO-1 could alleviate inflammation through the inhibition of p65 translocation, thus inhibiting NFKB pathways [ 27 , 119 , 120 ]. Notably, CAPE and lutein directly interact with the Keap1-NRF2 complex by inhibiting ubiquitination, resulting in Nrf2 stabilization and promoting the nuclear translocation of NRF2 [ 25 , 140 ].…”

“…Moreover, xanthohumol promotes the binding of HO-1 and C/EBPβ and inhibits C/EBPβ nuclear translocation [ 142 ]. The relevance of Nrf2 and/or HO1 signaling, upstream to NF-κB signaling inhibition, was proven by loss of function experiments using silencing [ 119 , 120 , 123 , 138 , 142 ]. Notably, Zhou et al depicted the interaction among NRF2 and AMPK signaling upon luteolin stimulation [ 140 ].…”

“…Al. found that tangeretin induces an anti-inflammatory effect and prevents OA, due to NF-κB inhibition, by simultaneously modulating Nrf2-HO-1/NF-κB and MAPK/NF-κB signaling pathways [ 120 ]. Teng et al showed that theaflavin-3-3′-gallate inhibited the PI3K/AKT/NF-κB and MAPK pathways while promoting the Nrf2/HO-1 pathway [ 123 ].…”