Glucagon-like peptide-1 receptor regulates endoplasmic reticulum stress-induced apoptosis and the associated inflammatory response in chondrocytes and the progression of osteoarthritis in rat

Abstract

Treatments for osteoarthritis (OA) are designed to restore chondrocyte function and inhibit cell apoptosis. Previous studies have shown that activation of the glucagon-like peptide-1 receptor (GLP-1R) leads to anti-inflammatory and anti-apoptotic effects. However, the role of GLP-1R in the pathological process of OA is unclear. In present work, we aimed to demonstrate the potential effect of GLP-1R on chondrocytes and elucidate its underlying mechanisms. We found that activation of GLP-1R with liraglutide could protect chondrocytes against endoplasmic reticulum stress and apoptosis induced by interleukin (IL)-1β or triglycerides (TGs). These effects were partially attenuated by GLP-1R small interfering RNA treatment. Moreover, inhibiting PI3K/Akt signaling abolished the protective effects of GLP-1R by increase the apoptosis activity and ER stress. Activating GLP-1R suppressed the nuclear factor kappa-B pathway, decreased the release of inflammatory mediators (IL-6, tumor necrosis factor α), and reduced matrix catabolism in TG-treated chondrocytes; these effects were abolished by GLP-1R knockdown. In the end, liraglutide attenuated rat cartilage degeneration in an OA model of knee joints in vivo. Our results indicate that GLP-1R is a therapeutic target for the treatment of OA, and that liraglutide could be a therapeutic candidate for this clinical application.

Dropping in on lipid droplets: insights into cellular stress and cancer

“…Despite the number of studies that suggest of its protective effects against ER stress, the abundance of cytoplasmic LDs appears to be selectively advantageous for cancer cells and is otherwise cytotoxic in normal cells. The incretin mimetic drug exendin-4 has been shown to reduce accumulation of ER stress-induced LDs with a concomitant decrease in UPR markers in cancer and non-cancer cells [ 57 , 58 ]. It exhibited anti-tumour effects [ 59 ] but promoted survival of normal cells [ 60–62 ].…”

Curcumin Inhibits the PERK-eIF2α-CHOP Pathway through Promoting SIRT1 Expression in Oxidative Stress-induced Rat Chondrocytes and Ameliorates Osteoarthritis Progression in a Rat Model

“…ER is a crucial tubular structure in chondrocytes on account of a mass of extracellular matrix (ECM) secreted by chondrocytes during the course of endochondral ossification [5]. Accumulation of ROS and UPR in the ER activates oxidative stress and ER stress, subsequently inducing the apoptosis of chondrocytes [7–9]. Accumulation of UPR is detected by three primary molecular sensors, including protein kinase RNA-like endoplasmic reticulum kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring protein-1 α (IRE1 α ) [10].…”

Exenatide ameliorates inflammatory response in human rheumatoid arthritis fibroblast‐like synoviocytes

“…Although GLP‐1 agonists are now widely used for the treatment of type II diabetes and are highly regarded for their ability to trigger insulin secretion from the pancreas, inhibit glucagon release, delay gastric emptying, and satiate hunger, a previous study showed that knockout of GLP‐1 in mice resulted in poor bone quality and reduced bone strength, thereby prompting investigations into the role of GLP‐1 in bone formation and remodeling . There have since been several studies demonstrating the antidegradative effects of exendin‐4 in osteoarthritis . Additionally, administration of GLP‐1 agonist has been shown to exert an anabolic effect on bone regeneration in obese type II diabetes patients with glucose intolerance .…”