Mechanical exposure and diacerein treatment modulates integrin-FAK-MAPKs mechanotransduction in human osteoarthritis chondrocytes

• Published in: Cellular signalling 2019-04, Vol.56, p.23-30
• Main Authors: Lohberger, Birgit, Kaltenegger, Heike, Weigl, Lukas, Mann, Anda, Kullich, Werner, Stuendl, Nicole, Leithner, Andreas, Steinecker-Frohnwieser, Bibiane
• Format: Article
• Language: English
• Subjects: ADAMTS Proteins - metabolism; Anthraquinones - pharmacology; Anti-Inflammatory Agents - pharmacology; Cell Line; Chondrocytes - pathology; Diacerein; Endopeptidases - metabolism; FAK; Focal Adhesion Kinase 1 - metabolism; Humans; Interleukin-6 - metabolism; Ion Channels - biosynthesis; MAPK signal transduction cascade; Matrix Metalloproteinases - metabolism; Mechanical stimulation; Mechanotransduction, Cellular - physiology; Osteoarthritis; Osteoarthritis - pathology; Piezo1; Signal Transduction - drug effects; STAT3 Transcription Factor - metabolism; Stress, Mechanical; Stress, Physiological - physiology; Thiolester Hydrolases - metabolism
• ISSN: 0898-6568; 1873-3913
• DOI: 10.1016/j.cellsig.2018.12.010

Progression of osteoarthritis (OA) is characterized by an excessive production of matrix degrading enzymes and insufficient matrix repair. Despite of active research in this area, it is still unclear how the combination of mechanical exposure and drug therapy works. This study was done to explore the impact of the disease modifying OA drug (DMOAD) diacerein and moderate tensile strain on the anabolic metabolism and the integrin-FAK-MAPKs signal transduction cascade of OA and non-OA chondrocytes. Cyclic tensile strain was applied in terms of three different intensities by the Flexcell tension system. Influence on catabolic parameters such as MMPs, ADAMTS, and IL-6 were assessed by qPCR. Changes in phosphorylation of FAK, STAT3 as well as MAP kinases were verified by western blot analysis. Intracellular calcium was measured fluorimetrically using fura-2. Tensile strain at moderate intensity (SM/SA profile) proved to be most efficient in terms of reducing production of matrix degrading enzyme and IL-6 expression. Treatment with diacerein by itself and diacerein in combination with SM/SA stimulation reduced phosphorylation of FAK and STAT3, which is more pronounced in OA cells. Pretreatment with diacerein for 7 days resulted in an increase in the sensitivity to Yoda1, the agonist for the mechanically activated ion channel Piezo1. However, in OA chondrocytes a significant reduction in Piezo1 expression was observed following treatment with diacerein. Our results demonstrated for the first time that diacerein intensively intervenes in the regulation of FAK and STAT3 and influences components considered relevant for the progression of OA, even in the presence of mechanical stimulation.