Cudratricusxanthone O Inhibits H2O2-Induced Cell Damage by Activating Nrf2/HO-1 Pathway in Human Chondrocytes

Abstract

Osteoarthritis (OA) is a common joint degenerative disease induced by oxidative stress in chondrocytes. Although induced-heme oxygenase-1 (HO-1) has been found to protect cells against oxygen radical damage, little information is available regarding the use of bioactive compounds from natural sources for regulating the HO-1 pathway to treat OA. In this study, we explored the inhibitory effects of cudratricusxanthone O (CTO) isolated from the Maclura tricuspidata Bureau (Moraceae) on H2O2-induced damage of SW1353 chondrocytes via regulation of the HO-1 pathway. CTO promoted HO-1 expression by enhancing the translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) into the nucleus without inducing toxicity. Pretreatment with CTO-regulated reactive oxygen species (ROS) production by inducing expression of antioxidant enzymes in H2O2-treated cells and maintained the functions of H2O2-damaged chondrocytes. Furthermore, CTO prevented H2O2-induced apoptosis by regulating the expression of anti-apoptotic proteins. Treatment with the HO-1 inhibitor tin-protoporphyrin IX revealed that these protective effects were exerted due to an increase in HO-1 expression induced by CTO. In conclusion, CTO protects chondrocytes from H2O2-induced damages—including ROS accumulation, dysfunction, and apoptosis through activation of the Nrf2/HO-1 signaling pathway in chondrocytes and, therefore, is a potential therapeutic agent for OA treatment.

Establishing SW1353 Chondrocytes as a Cellular Model of Chondrolysis

“…These changes were accompanied by an increase in 8-isoprostane F2-α levels but a lower level of intracellular TNF-α. Previous studies showed that the IC 50 values of H 2 O 2 in SW1353 chondrocytes ranged from 0.5 to 1 mM upon 1 h to 24 h of treatment [ 15 , 37 , 38 , 39 ], while IC 50 values around 5–8.26 µM for MIA were reported for SW1353 chondrocytes [ 16 , 43 ] and primary chondrocytes [ 17 , 46 , 87 ]. Our data demonstrated that IC 50 values of H 2 O 2 and MIA were 82.5 µM (6- to 12-fold lower) and 31.5 µM (4- to 6-fold higher), respectively.…”

“…The use of commercially available chondrocyte cell lines could overcome these limitations because they are readily available, cost-effective, technically less challenging to culture and without significant ethical issues compared with primary chondrocytes. Several human chondrocyte cell lines have been used as in vitro OA models, including SW1353 chondrocytes [ 15 , 16 , 17 ], CHON-001 cells [ 18 , 19 ], CHON-002 cells [ 20 ], and C-28/I2, T/C-28a2 and T/C-28a4 chondrocytes [ 21 , 22 ].…”

“…Chondrosarcoma cell line SW1353 is one of the most common and established cell lines used as in vitro OA model [ 15 , 16 , 17 , 23 ]; its first use in an interleukin (IL)-1-induced inflammation model was recorded in 1987 [ 24 ]. To mimic the initiation and pathogenesis of OA, SW1353 chondrocytes are generally stimulated with proinflammatory cytokines like IL-1β or TNF-α to trigger the inflammatory response and catabolic profile, marked by upregulation of MMPs and cytokine production [ 25 , 26 ].…”

“…H 2 O 2 is membrane-permeable [ 33 ], whereby it can cross the plasma membrane and cause oxidative damage and cell death [ 34 ]. The cytotoxicity of H 2 O 2 has been reported in primary articular chondrocytes from animals and humans [ 34 , 35 ], human C28/12 chondrocytes [ 36 ] and SW1353 chondrocytes [ 15 , 37 , 38 , 39 ]. The functionality and telomere stability of surviving chondrocytes were also affected [ 40 ].…”

Oxidative Stress Modulators and Functional Foods

“…Osteoarthritis (OA) is a common joint degenerative disease induced by oxidative stress in chondrocytes. Kim et al [ 6 ] demonstrated the inhibitory effects of cudratricusxanthone O (CTO), isolated from the Maclura tricuspidata Bureau (Moraceae), on the H 2 O 2 -induced damage of SW1353 chondrocytes. CTO induced HO-1 expression, involving the translocation of Nrf2 into the nucleus.…”