Safranal Treatment Induces Sirt1 Expression and Inhibits Endoplasmic Reticulum Stress in Mouse Chondrocytes and Alleviates Osteoarthritis Progression in a Mouse Model

Abstract

Osteoarthritis (OA) is an age-related degenerative disease. Oxidative stress (OS) modulates OA pathogenesis by enhancing chondrocyte apoptosis and extracellular matrix (ECM) degeneration via activation of the endoplasmic reticulum (ER) stress. Prior studies revealed that safranal plays a critical role in multiple diseases treatments, but there are no reports on its effect on OA. Therefore, investigating the effect of safranal on OA is needed. As a compound that can lead excessive reactive oxygen species (ROS) accumulation, tert-butyl hydroperoxide (TBHP) was used to induce OS and OS-mediated endoplasmic reticulum (ER) stress for imitating OA in vitro. Besides, the bilateral medial meniscus was removed to induce joint instability and excessive friction of the joint surface to establish destabilization of medial meniscus for imitating the initiation and progression of OA in vivo. We, next, conducted Western blot and RT-PCR analyses to identify biomarkers of the underlying signaling pathway. Our results demonstrated that 30 μM safranal strongly upregulated Sirt1 expression, suppressed TBHP-mediated ER stress, and, in turn, prevented chondrocyte apoptosis and ECM degeneration. Furthermore, compared with the other two classic signaling pathways of ER stress, safranal can inhibit the PERK-eIF2α-CHOP axis at the lower concentration (5 and 15 μM). In vivo, using Safranin O staining, X-ray, immunofluorescence (IF), and immunohistochemical (IHC) staining, we demonstrated that OA progression can be postponed with intraperitoneal injection of 90 and 180 mg/kg safranal in an OA mouse model. Taken together, our analyses revealed that safranal can potentially prevent OA development.

Cardamonin protects against iron overload induced arthritis by attenuating ROS production and NLRP3 inflammasome activation via the SIRT1/p38MAPK signaling pathway

“…And ow cytometry revealed inhibition of chondrocyte apoptosis. Moreover, studies have reported that decreased SIRT1 expression leads to increased ROS levels in chondrocytes 35 , whereas our experimental results revealed that CAR reduced ROS levels in chondrocytes, which may be related to the activation of SIRT1 by CAR. Thus, CAR protects chondrocytes against iron overload-induced apoptosis via the SIRT1 signaling pathway.…”

Chrysin ameliorates synovitis and fibrosis of osteoarthritic fibroblast-like synoviocytes in rats through PERK/TXNIP/NLRP3 signaling

“…These three receptors are inactive under physiological conditions by binding to glucose regulated protein 78/immunoglobulin binding protein (GRP78/BiP) ( Huang et al, 2022 ). When endoplasmic reticulum stress is stimulated, GRP78 is activated and dissociates, and PERK catalyzes eukaryotic translation initiation factor 2α (eIF2-α) phosphorylation, increases CCAAT/enhancer-binding protein homologous protein (CHOP) expression, and activates the TXNIP-NLRP3 inflammatory vesicle complex, which ultimately leads to inflammation and fibrosis ( Ayaub et al, 2016 ; Wu et al, 2018 ; Zhang et al, 2022b ; Dong et al, 2022 ). In our study, we proved that CHR inhibited the expression of GRP78, ATF-6, TXNIP and the overproduction of PERK, IRE1α, CHOP, TXNIP and NLRP3 at the protein and mRNA levels.…”

Ginsenoside Compound K Ameliorates Osteoarthritis by Inhibiting the Chondrocyte Endoplasmic Reticulum Stress-Mediated IRE1α-TXNIP-NLRP3 Axis and Pyroptosis

“…Tissue loss under normal physiological conditions can be compensated by the new matrix molecules synthesized by the chondrocytes . However, the high levels of matrix loss, previously thought to be a result of OA, that exceed the ability of chondrocytes to synthesize the matrix result in misfolded protein accumulation . Misfolded proteins can be recognized by specific stress sensors, and the unfolded protein response is initiated.…”

“…33 However, the high levels of matrix loss, previously thought to be a result of OA, that exceed the ability of chondrocytes to synthesize the matrix result in misfolded protein accumulation. 34 Misfolded proteins can be recognized by specific stress sensors, and the unfolded protein response is initiated. The molecular chaperone BiP, which binds to ATF6, PERK, and IRE1 in the endoplasmic reticulum membrane, dislocates from these molecules and binds to misfolded proteins.…”