Abstract
BackgroundAutophagy induction is an effective approach for OA therapy. IL-1β is one of the major inflammatory cytokines linked to OA pathological progression, and its receptor blockade interrupts OA cartilage destruction. The objective of this study was to decipher the link between autophagy and regulatory mechanism of IL-1β and to investigate the effect of IL-1β receptor blockade by IL-1 receptor antagonist (IL-1Ra) combined with or without an autophagy inducer (TAT-Beclin1) on extracellular matrix (ECM) in OA chondrocytes in vitro and in vivo.MethodsIL-1β-treated rat and human OA chondrocytes were cultured in response to IL-1Ra. The expression and distribution of signal molecules regulating ECM synthesis and autophagy were investigated via western blotting, immunoprecipitation, real-time PCR, immunofluorescence, and transmission electron microscope technique. Furthermore, after intra-articular injection of IL-1Ra, TAT-Beclin1, and a combination of both in a rat OA model established by anterior cruciate ligament transection and medial meniscus resection, the morphological changes of cartilage and related signal molecule expression levels were monitored using H.E., Safranin O-Fast green, and immunohistochemistry staining.ResultsReduced autophagy by IL-1β contributed to ECM degradation, and blockade of IL-1β by IL-1Ra restored autophagy and attenuated ECM degradation in rat and human OA chondrocytes, as well as in a rat OA model. Akt/mTOR/ULK1, Akt/mTOR/NF-κB, and LC3B deacetylation were involved in autophagy regulated by IL-1β. Intra-articular injection of IL-1Ra combined with TAT-Beclin1 was more effective than IL-1Ra alone.ConclusionsIL-1Ra restored autophagy and attenuated ECM degradation, with an implication that blocking IL-1β combined with enhancing autophagy might be a potential therapeutic strategy for OA.
Highlights
Autophagy induction is an effective approach for OA therapy
IL-1 receptor blockade by IL-1 receptor antagonist (IL-1Ra) restored autophagy to attenuate extracellular matrix (ECM) degradation in rat OA chondrocytes In rat chondrocytes, IL-1β significantly reduced Beclin1 protein level and the ratio of Autophagy marker light chain 3B (LC3B)-Type II of collagen (II)/I, along with a significant decrease in Col II protein level, while Aggrecan expression level failed to show a significant difference (Fig. 1a, *p < 0.05, **p < 0.01, ***p < 0.001, vs control chondrocytes)
Our findings demonstrated that IL-1β degraded ECM synthesis concomitant with reduced autophagy in IL1β-treated rat and human OA chondrocytes
Summary
IL-1β is one of the major inflammatory cytokines linked to OA pathological progression, and its receptor blockade interrupts OA cartilage destruction. The objective of this study was to decipher the link between autophagy and regulatory mechanism of IL-1β and to investigate the effect of IL-1β receptor blockade by IL-1 receptor antagonist (IL-1Ra) combined with or without an autophagy inducer (TAT-Beclin1) on extracellular matrix (ECM) in OA chondrocytes in vitro and in vivo. IL-1β is produced by activated synoviocytes and mononuclear cells, and by articular cartilage chondrocytes [1]. It could significantly upregulate metalloproteinase (MMP) gene expression, resulting in extracellular matrix (ECM) degradation [2]. The mechanism of blocking IL-1β by IL1Ra to promote cartilage regeneration is not fully understood [4]
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