Extracellular and Intracellular Mechanisms of Mechanotransduction in Three-Dimensionally Embedded Rat Chondrocytes |
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Authors: | Suguru Shioji Shinji Imai Kosei Ando Kousuke Kumagai Yoshitaka Matsusue |
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Institution: | Department of Orthopedic Surgery, Shiga University of Medical Science, Otsu, Shiga, Japan.; University of Maryland School of Medicine, United States of America, |
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Abstract: | PurposeArticular cartilage homeostasis involves modulation of chondrocyte matrix synthesis in response to mechanical stress (MS). We studied extracellular and intracellular mechanotransduction pathways mediating this response.MethodsWe first confirmed rapid up-regulation of the putative chondro-protective cytokine, interleukin (IL)-4, as an immediate response to MS. We then studied the role of IL-4 by investigating responses to exogenous IL-4 or a specific IL-4 inhibitor, combined with MS. Next we investigated the intracellular second messengers. Since chondrocyte phenotype alters according to the extracellular environment, we characterized the response to mechanotransduction in 3-dimensionally embedded chondrocytes.ResultsExpression of aggrecan and type II collagen was significantly up-regulated by exogenous IL-4 whereas MS-induced matrix synthesis was inhibited by an IL-4 blocker. Further, MS-induced matrix synthesis was completely blocked by a p38 MAPK inhibitor, while it was only partially blocked by inhibitors of other putative second messengers.ConclusionIL-4 mediates an extracellular pathway of mechanotransduction, perhaps via an autocrine/paracrine loop, while p38 mediates an intracellular pathway prevalent only in a 3-dimensional environment. |
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