Cyclic Tensile Strain Upregulates Pro-Inflammatory Cytokine Expression Via FAK-MAPK Signaling in Chondrocytes
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ORIGINAL ARTICLE
Cyclic Tensile Strain Upregulates Pro-Inflammatory Cytokine Expression Via FAK-MAPK Signaling in Chondrocytes Makoto Yanoshita,1 Naoto Hirose,1,3 Yuki Okamoto,2 Chikako Sumi,1 Mami Takano,1 Sayuri Nishiyama,1 Yuki Asakawa-Tanne,1 Kayo Horie,1 Azusa Onishi,1 Yuka Yamauchi,1 Tomomi Mitsuyoshi,2 Ryo Kunimatsu,2 and Kotaro Tanimoto1
Excessive mechanical stimulation is considered an important factor in the destruction of chondrocytes. Focal adhesion kinase (FAK) is non-receptor tyrosine kinase related to a number of different signaling proteins. Little is known about the function of FAK in chondrocytes under mechanical stimulation. In the present study, we investigated the function of FAK in mechanical signal transduction and the mechanism through which cyclic tensile strain (CTS) induces expression of inflammation-related factors. Mouse ATDC5 chondrogenic cells were subjected to CTS of 0.5 Hz to 10% cell elongation with an FAK inhibitor. The expression of genes encoding COX-2, IL-1β, and TNF-α was examined using real-time RT-PCR after CTS application with FAK inhibitor. Phosphorylation of p-38, ERK, and JNK was analyzed by Western blotting. Differences in COX-2 expression following pretreatment with FAK, p-38, ERK, and JNK inhibitors were compared by Western blotting. We found that CTS increased the expression of genes encoding COX-2, IL-1β, and TNF-α and activated the phosphorylation of FAK, p-38, ERK, and JNK. Pretreatment with an FAK inhibitor for 2 h reduced the expression of genes encoding COX-2, IL-1β, and TNF-α induced by CTS-associated inflammation and decreased phosphorylation of FAK, p-38, ERK, and JNK. Pretreatment with FAK, p-38, ERK, and JNK inhibitors markedly suppressed COX-2 and IL-1β protein expression. In conclusion, FAK appears to regulate inflammation in chondrocytes under CTS via MAPK pathways.
Abstract—
KEY WORDS: focal adhesion kinase; chondrocyte; mechanical stimulation; mitogen-activated protein kinases.
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10753-018-0805-8) contains supplementary material, which is available to authorized users. 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, Japan 2 Department of Orthodontics, Division of Oral Health and Development, Hiroshima University Hospital, Hiroshima, Japan 3 To whom correspondence should be addressed at 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, Japan. E-mail: [email protected]
INTRODUCTION Mechanical stimulation is an important factor controlling the proliferation and differentiation of chondrocytes [1]. Several studies have reported that excessive mechanical stimulation in cartilage is associated with chondrocyte destruction. An optimal level of mechanical
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