1. Academic Validation
  2. Protective effects of cilengitide on inflammation in chondrocytes under excessive mechanical stress

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

  • Cell Biol Int. 2020 Apr;44(4):966-974. doi: 10.1002/cbin.11293.
Naoto Hirose 1 Yuki Okamoto 2 Makoto Yanoshita 2 Yuki Asakawa 1 Chikako Sumi 2 Mami Takano 1 Sayuri Nishiyama 1 Shao-Ching Su 1 Tomomi Mitsuyoshi 1 Ryo Kunimatsu 2 Kazuo Tanne 1 Kotaro Tanimoto 1
Affiliations

Affiliations

  • 1 Department of Orthodontics and Craniofacial Developmental Biology, Hiroshima University Graduate School of Biomedical and Health Sciences, Kasumi 1-2-3 Minami-ku, Hiroshima-shi, Hiroshima prefecture, 7348551, Japan.
  • 2 Department of Orthodontics, Division of Oral Health and Development, Hiroshima University Hospital, Hiroshima, Japan.
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.

Keywords

chondrocyte; cilengitide; inflammation; integrins αVβ3 and αVβ5; mechanical stress.

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