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.
Highlights
Osteoarthritis (OA) is a prevalent progressive and degenerative joint disease that results in personal activity limitations, disability, and great economic burden worldwide[1]
Western blotting data demonstrated that the expression of glucagon-like peptide-1 receptor (GLP-1R) was lower in response to IL-1β stimulation than control group (Fig. 1c, d)
To explore whether the protective effects of GLP-1R were modulated by PI3K/Akt signal pathway, LY294002, a specific PI3K inhibitor was used to treat chondrocytes combined with liraglutide treatment
Summary
Osteoarthritis (OA) is a prevalent progressive and degenerative joint disease that results in personal activity limitations, disability, and great economic burden worldwide[1]. Various factors contribute to the initiation and Official journal of the Cell Death Differentiation Association. Chen et al Cell Death and Disease (2018)9:212. Previous study showed that systematic blockade of IL-6 reduced expression of MMPs and ADAMTSs (a disintegrin and metalloproteinase with thrombospondin motifs) could alleviate medial meniscus-induced OA cartilage lesions[8]. Accumulation of misfolded proteins in the ER triggers the unfolded protein response (UPR), in which C/EBP homologous protein (CHOP) is activated, subsequently activating the caspase family and inducing chondrocyte death[12]. It has been reported that the pro-inflammatory factor IL-1β induces ER stress-related apoptosis in cultured chondrocytes[14]. IL-1β plays a critical role in the initiation of OA; evidence suggests that IL-1β can accelerate anabolic activities in chondrocytes[15]. IL-1β was used to induce ER stress and subsequent apoptosis
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
