Icariin Activates Autophagy via Down-Regulation of the NF-κB Signaling-Mediated Apoptosis in Chondrocytes

Abstract

Osteoarthritis (OA) is a common chronic and degenerative joint condition that is mainly characterized by cartilage degradation, osteophyte formation, and joint stiffness. The NF-κB signaling pathway in inflammation, autophagy, and apoptosis plays a prominent role in the progression of OA. Icariin, a prenylated flavonol glycoside extracted from Epimedium, have been proven to exert anti-osteoporotic and anti-inflammatory effects in OA. However, the action mechanisms of its effect on chondrocytes have yet to be elucidated. In the present study, we demonstrated that the in vitro therapeutic effects of icariin on rat chondrocytes in a dose-dependent manner. We found that TNF-α induced the production of IL-1, IL-6, IL-12, reactive oxygen species (ROS), nitric oxide (NO), Caspase-3, and Caspase-9 in chondrocytes. We also provided evidence that TNF-α inhibited autophagy markers (Atg 5, Atg 7) and prevented LC3 I translate to LC3 II. Furthermore, TNF-α induced matrix metalloproteinase (MMP)3 and MMP9 expression. The negative effects of TNF-α on chondrocytes can be partially blocked by treating with icariin or ammonium pyrrolidinedithiocarbamate (PDTC, an NF-κB inhibitor). The present study data also suggested that icariin suppressed both TNF-α-stimulated p65 nuclear translocation and IκBα protein degradation. These results indicated that icariin protected against OA by suppressing inflammatory cytokines and apoptosis, through activation of autophagy via NF-κB inhibition. In conclusion, icariin appears to favorably modulate autophagy and apoptosis in chondrocytes making it a promising compound for cartilage tissue engineering in the treatment of OA.

Polysaccharide from angelica sinensis attenuates SNP-Induced Apoptosis in osteoarthritis Chondrocytes by Inducing Autophagy via ERK1/2 Pathway

“…In addition, Li X et al reported that the ERK1/2 signaling pathways activation was involved in chondrocyte autophagy, which protected chondrocyte from apoptosis [41]. Moreover, Pathways such as AMPK/mTOR [42], PI3K/AKT [43], and AKT/mTOR [39] were associated with autophagy in chondrocytes. We found that ASP -induced autophagy plays a critical role in the prevention of SNPinduced apoptosis via the ERK1/2 signaling pathway (Fig.…”

“…Autophagy is regulated by multiple signaling pathways in chondrocytes. Inhibition of NF-κB pathway promotes the expression of Atg5, Atg7, and LC3II, and activates autophagy [39]. Shi et al showed that autophagy levels were signi cantly inhibited after activation of the p38 signaling pathway in osteoarthritis [40].…”

Icariin alleviates osteoarthritis by inhibiting NLRP3-mediated pyroptosis

“…ICA, the extract of Epimedium, is known to have anti-oxidative, anti-neuroinflammatory, and anti-apoptotic effects and considered to be effective for a range of disorders, such as neoplasm, Alzheimer's disease, cerebral ischemia, depression, diabetes, and Parkinson's disease (PD) [22][23][24][25]. For OA, ICA was identified as an anti-osteoporotic and anti-inflammatory compound through multi-target mechanisms, including the suppression of NF-κB signaling and inhibition of MMP1, MMP3, and MMP13 expression or OPG-RANKL-RANK system via MAPK pathways [13][14][15]. The present study demonstrated that ICA inhibited LPS-mediated chondrocytes injury and pyroptosis and alleviated rat osteoarthritis by inhibiting NLRP3 and caspase-1 signaling.…”

“…Icariin (ICA) which is the extract of Epimedium was identified as the effective constituent, showing anti-osteoporotic and anti-inflammatory effects [12]. Studies revealed that ICA prevented OA inflammation and chondrocytes apoptosis though activation of autophagy via inhibiting NF-κB signaling pathway [13]. Furthermore, ICA exerted a chondroprotective effect through the inhibition of MMP-1, MMP-3, and MMP-13 or the suppression of osteoprotegerin (OPG), receptor activator of nuclear factor kappa-B ligand (RANKL), and receptor activator of nuclear factor kappa-B (RANK) system via MAPK pathway in IL-1β-stimulated chondrosarcoma cells [14,15].…”

Icariin Attenuates High Glucose-Induced Apoptosis, Oxidative Stress, and Inflammation in Human Umbilical Venous Endothelial Cells

“…In cancer cells, icariin displays anticancer activity by significantly promoting apoptosis [25,26]. In contrast, icariin protects normal cells against cell apoptosis induced by various stimuli, including HG [27,28]. More studies are necessary to elucidate the mechanism underlying this discrepancy.…”