Function of the chondrocyte PI-3 kinase-Akt signaling pathway is stimulus dependent

Objective: The PI-3 kinase-Akt pathway plays a role in cartilage anabolic as well as catabolic processes in response to activation by insulin-like growth factor-1 (IGF-1) and the pro-inflammatory cytokines interleukin-1 beta (IL-1 beta) and oncostatin M (OSM). The goal of this study was to determine how PI-3 kinase-Akt signaling regulates these seemingly opposing functions. Design: Monolayer cultures of primary human articular chondrocytes were treated with IGF-1, IL-1 beta, OSM, or the combination of IL-1 beta and OSM in time course experiments. Activation of signaling proteins and MMP production were measured by immunoblotting. Cells were pre-treated with chemical inhibitors to block mitogen activated protein (MAP) kinases, PI-3 kinase, or JAK/STAT pathway activation. Constitutively active Akt1 and Akt3 were expressed to study stimulus-independent activation of Akt. Results: IGF-1, OSM, and the combination of IL-1 beta and OSM but not IL-1 beta alone, stimulated phosphorylation of Akt which was sustained longer with IGF-1. IL-1 beta plus OSM, but not IGF-1, increased chondrocyte MMP-13 production which was inhibited with either a general PI-3 kinase inhibitor or specific inhibition of the PI-3 kinase-gamma isoform. Akt1 or Akt3 activity alone was not sufficient to increase production of MMP-13. IL-1 beta/OSM induced MMP-13 production required activation of the MAP kinases, JNK and p38, as well as the JAK-STAT pathway which were activated by IL-1 beta plus OSM but not by IGF-1. Conclusions: The chondrocyte integrates signals from the PI-3 kinase-Akt pathway with signals from MAP kinases and the JAK-STAT pathway to allow for a differential response to a pro-anabolic (IGF-1) and a pro-catabolic (IL-1 beta plus OSM) stimulus. (C) 2015 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.