Artemisinin relieves osteoarthritis by activating mitochondrial autophagy through reducing TNFSF11 expression and inhibiting PI3K/AKT/mTOR signaling in cartilage.
Osteoarthritis (OA) is a widespread chronic degenerative joint disease characterized by the degeneration of articular cartilage or inflamed joints. Our findings indicated that treatment with artemisinin (AT) downregulates the protein levels of MMP3, MMP13, and ADAMTS5, which are cartilage degradation-related proteins in OA, and inhibits the expression of inflammatory factors in interleukin-1β (IL-1β)-stimulated chondrocytes. However, the mechanism of the role of AT in OA remains unclear. Here, we performed gene sequencing and bioinformatics analysis in control, OA, and OA + AT groups to demonstrate that several mRNA candidates were enriched in the PI3K/AKT/mTOR signaling pathway, and TNFSF11 was significantly downregulated after AT treatment. TNFSF11 was downregulated in the OA + AT group, whereas it was upregulated in rat OA tissues and OA chondrocytes. Therefore, we confirmed that TNFSF11 was the target gene of AT. In addition, our study revealed that AT relieved cartilage degradation and defection by activating mitochondrial autophagy via inhibiting the PI3K/AKT/mTOR signaling pathway in IL-1β-induced chondrocytes. Furthermore, an OA model was established in rats with medial meniscus destabilization. Injecting AT into the knee joints of OA rat alleviated surgical resection-induced cartilage destruction. Thus, these findings revealed that AT relieves OA by activating mitochondrial autophagy by reducing TNFSF11 expression and inhibiting PI3K/AKT/mTOR signaling.
Li J
，Jiang M
，Yu Z
，Xiong C
，Pan J
，Cai Z
，Xu N
，Zhou X
，Huang Y
，Yang Z
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Silencing UHRF1 enhances cell autophagy to prevent articular chondrocytes from apoptosis in osteoarthritis through PI3K/AKT/mTOR signaling pathway.
Osteoarthritis (OA) is a common chronic degenerative joint disease, and chondrocyte apoptosis is one of most important pathological changes of OA pathogenesis. Growing studies have shown that Ubiquitin-like with PHD and RING finger domains 1 (UHRF1) is an important epigenetic regulatory factor that regulates cell proliferation and apoptosis of various tumors, but its role in OA remains ill-defined. In the present study, we found that UHRF1 expression was increased in human OA cartilage tissues, compared with normal cartilage tissues. Interleukin-1β (IL-1β), a major inflammatory cytokine that promotes cartilage degradation in OA, was used to stimulate primary human chondrocytes in vitro. The expression of UHRF1 was also enhanced in IL-1β-induced chondrocytes. Moreover, down-regulation of UHRF1 induced an increase on cell proliferation and autophagy, and a decrease on apoptosis of chondrocytes after IL-1β treatment. Further data indicated that silencing UHRF1 attenuated the up-regulation of IL-1β on phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway in chondrocytes. Then, an activator of PI3K weakened the effect of UHRF1 silencing on cell proliferation, autophagy, apoptosis of IL-1β-induced chondrocytes, and the cell autophagy special inhibitor 3-methyladenine (3-MA) also showed a same impact on UHRF1, hence suggesting that knockdown of UHRF1 enhances cell autophagy to protect chondrocytes from apoptosis in OA through PI3K/AKT/mTOR signaling pathway. In conclusion, our study suggests that UHRF1 may be a potential regulator of chondrocyte apoptosis in the pathogenesis of OA.
Shi X
，Han L
，Sun T
，Zhang F
，Ji S
，Zhang M
，Wang X
，Yang W
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microRNA-206 is required for osteoarthritis development through its effect on apoptosis and autophagy of articular chondrocytes via modulating the phosphoinositide 3-kinase/protein kinase B-mTOR pathway by targeting insulin-like growth factor-1.
microRNA (miR) has been shown to be involved in the treatment of diseases such as osteoarthritis (OA). This study aims to investigate the role of miR-206 in regulating insulin-like growth factor-1 (IGF-1) in chondrocyte autophagy and apoptosis in an OA rat model via the phosphoinositide 3-kinase (P13K)/protein kinase B (AKT)-mechanistic target of rapamycin (mTOR) signaling pathway. Wistar rats were used to establish the OA rat model, followed by the observation of histopathological changes, Mankin score, and the detection of IGF-1-positive expression and tissue apoptosis. The underlying regulatory mechanisms of miR-206 were analyzed in concert with treatment by an miR-206 mimic, an miR-206 inhibitor, or small interfering RNA against IGF-1 in chondrocytes isolated from OA rats. Then, the expression of miR-206, IGF-1, and related factors in the signaling pathway, cell cycle, and apoptosis, as well as inflammatory factors, were determined. Subsequently, chondrocyte proliferation, cell cycle distribution, apoptosis, autophagy, and autolysosome were measured. OA articular cartilage tissue exhibited a higher Mankin score, promoted cell apoptotic rate, increased expression of IGF-1, Beclin1, light chain 3 (LC3), Unc-51-like autophagy activating kinase 1 (ULK1), autophagy-related 5 (Atg5), caspase-3, and Bax, yet exhibited decreased expression of miR-206, P13K, AKT, mTOR, and Bcl-2. Besides, miR-206 downregulated the expression of IGF-1 and activated the P13K/AKT signaling pathway. Moreover, miR-206 overexpression and IGF-1 silencing inhibited the interleukins levels (IL-6, IL-17, and IL-18), cell apoptotic rate, the formation of autolysosome, and cell autophagy while promoting the expression of IL-1β and cell proliferation. The findings from our study provide a basis for the efficient treatment of OA by investigating the inhibitory effects of miR-206 on autophagy and apoptosis of articular cartilage in OA via activating the IGF-1-mediated PI3K/AKT-mTOR signaling pathway.
Yu Q
，Zhao B
，He Q
，Zhang Y
，Peng XB
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