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-1β (IL-1β) 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-1β, OSM, or the combination of IL-1β 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-1β and OSM but not IL-1β alone, stimulated phosphorylation of Akt which was sustained longer with IGF-1. IL-1β 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-γ isoform. Akt1 or Akt3 activity alone was not sufficient to increase production of MMP-13. IL-1β/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-1β 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-1β plus OSM) stimulus.