Protective effects of cilengitide on inflammation in chondrocytes under excessive mechanical stress

Abstract

Chondrocytes constantly receive external stimuli, which regulates remodeling. An optimal level of mechanical stress is essential for maintaining chondrocyte homeostasis, however, excessive mechanical stress induces inflammatory cytokines and protease, such as matrix metalloproteinases (MMPs). Therefore, excessive mechanical stress is considered to be one of the main causes to cartilage destruction leading to osteoarthritis (OA). Integrins are well‐known as cell adhesion molecules and act as receptors for extracellular matrix (ECM), and are believed to control intracellular signaling pathways both physically and chemically as a mechanoreceptor. However, few studies have focused on the roles and functions of integrins in inflammation caused by excessive mechanical stress. In this study, we examined the relationship between integrins (αVβ3 and αVβ5) and the expression of inflammatory factors under mechanical loading in chondrocytes by using an integrin receptor antagonist (cilengitide). Cilengitide suppressed the gene expression of interleukin‐1β (IL‐1β), tumor necrosis factor‐α (TNF‐α), matrix metalloproteinase‐3 (MMP‐3), and MMP‐13 induced by excessive mechanical stress. In addition, the protein expression of IL1‐β and MMP‐13 was also inhibited by the addition of cilengitide. Next, we investigated the involvement of intracellular signaling pathways in stress‐induced integrin signaling in chondrocytes by using western blotting. The levels of p‐FAK, p‐ERK, p‐JNK, and p‐p38 were enhanced by excessive mechanical stress and the enhancement was suppressed by treatment with cilengitide. In conclusion, this study revealed that excessive mechanical stress may activate integrins αVβ3 and αVβ5 on the surface of chondrocytes and thereby induce an inflammatory reaction by upregulating the expression of IL‐1β, TNF‐α, MMP‐3, and MMP‐13 through phosphorylation of FAK and MAPKs.

Formula Diet Alters the Ileal Metagenome and Transcriptome at Weaning and during the Postweaning Period in a Porcine Model

“…Disrupted tight junction signaling in mucosa could possibly explain a response to the breakdown of the integrity of epithelial tight junctions (50). Notably, the current study indicated that MF diet reduced the expression of genes involved in key pathways (epithelial adherens junction, integrin, and ILK signaling) that regulate tight junctions in IL (51,52). Several pathogens invade hosts by taking advantage of the dysregulation of tight junctions in mucosal cells (53).…”

Molecular mechanisms of mechanical load-induced osteoarthritis

“…Besides, integrin-fibrin-α5β1 axis detects mechanical signals and increases the expression of matrix degrading enzymes, MMP3, and MMP13 [66]. Hirose et al [67] showed that integrin inhibitor cilengitide significantly downregulated several inflammatory factors such as IL-1β, TNF-α, MMPs, p-FAK, p-ERK, JNK, and p-p38 that were upregulated by overloading. Moreover, ion channels play important roles in mechanical signal transduction.…”

Comprehensive evaluation of differential long non‑coding RNA and gene expression in patients with cartilaginous endplate degeneration of cervical vertebra

“…Integrins are well-known as cell adhesion molecules and act via ECM-receptor interaction (31). Moreover, integrins are suggested to control intracellular signaling pathways both physically and chemically as mechanoreceptors (32). Previous studies have reported that if the fibrillar network of the ECM is dysfunctional or assembled from fibers that cannot bind and activate α5β1 integrins, chondrocytes increase the MMP expression, which inhibits cartilage regeneration (33).…”