Echinacoside Upregulates Sirt1 to Suppress Endoplasmic Reticulum Stress and Inhibit Extracellular Matrix Degradation In Vitro and Ameliorates Osteoarthritis In Vivo

Abstract

Background. Osteoarthritis (OA) is a progressive illness that destroys cartilage. Oxidative stress is a major contributor of OA, while endoplasmic reticulum (ER) stress is the key cellular damage under oxidative stress in chondrocytes. Echinacoside (ECH) is the main extract and active substance of Cistanche, with potent antioxidative stress (OS) properties, and currently under clinical trials in China. However, its function in OA is yet to be determined. Purpose. We aimed to explore the specific role of ECH in the occurrence and development of OA and its underlying mechanism in vivo and in vitro. Methods. After the mice were anesthetized, the bilateral medial knee joint meniscus resection was performed to establish the DMM model. TBHP was used to induce oxidative stress to establish the OA model in chondrocytes in vitro. Western blot and RT-PCR were used to evaluate the level of ER stress-related biomarkers such as p-PERK/PERK, GRP78, ATF4, p-eIF2α/eIF2α, and CHOP and apoptosis-related proteins such as BAX, Bcl-2, and cleaved caspase-3. Meanwhile, we used SO staining, immunofluorescence, and immunohistochemical staining to evaluate the pharmacological effects of ECH in mice in vivo. Results. We demonstrated the effectiveness of ECH in suppressing ER stress and restoring ECM metabolism in vitro. In particular, ECH was shown to suppress tert-Butyl hydroperoxide- (TBHP-) induced OS and subsequently lower the levels of p-PERK/PERK, GRP78, ATF4, p-eIF2α/eIF2α, and CHOP in vitro. Simultaneously, ECH reduced MMP13 and ADAMTS5 levels and promoted Aggrecan and Collagen II levels, suggesting ECM degradation suppression. Moreover, we showed that ECH mediates its cellular effects via upregulation of Sirt1. Lastly, we confirmed that ECH can protect against OA in mouse OA models. Conclusion. In summary, our findings indicate that ECH can inhibit ER stress and ECM degradation by upregulating Sirt1 in mouse chondrocytes treated with TBHP. It can also prevent OA development in vivo.

Fluoride Exposure Suppresses Proliferation and Enhances Endoplasmic Reticulum Stress and Apoptosis Pathways in Hepatocytes by Downregulating Sirtuin-1

“…Besides, Sirt-1 also can exert a protective role against liver injury by suppressing ERS [ 23 ]. Recent study also revealed that Sirt-1 can weaken ERS by inhibiting the protein kinase R- (PKR-) like endoplasmic reticulum kinase- (PERK-) eIF2 α -activating transcription factor 4 (ATF4) pathway, ultimately reducing ERS-induced apoptosis [ 24 ]. However, whether Sirt-1 can be involved in fluorine exposure-induced ERS in hepatocytes is not fully understood.…”

Excessive sulfur oxidation in endoplasmic reticulum drives an inflammatory reaction of chondrocytes in aging mice

“…It has been reported that endoplasmic reticulum oxidative stress occurs in articular chondrocytes of OA patients, which promotes apoptosis of chondrocytes ( Bian et al, 2018 ), ( Cao et al, 2018 ). After treatment with antioxidants, they can protect the chondrocytes, thus alleviating disease ( Fu et al, 2022 ), ( Hecht et al, 2021 ), ( Lin et al, 2021 ). Therefore, we conducted a further study on the causes of endoplasmic reticulum stress.…”

Gingko biloba-inspired lactone prevents osteoarthritis by activating the AMPK-SIRT1 signaling pathway

“…Intriguingly, the adiponectin-AdipoR1-AMPK axis has been linked to MMP3 activation and cartilage destruction [ 40 ]. As a longevity code, SIRT1 regulates the chondrogenic fate of mesenchymal stem cells [ 41 ] as well as the homeostasis of cartilage ECM synthesis and degradation [ 42 ]. The effects of BB on SIRT1 and the underlying mechanisms involved have not been studied.…”