title: Function of the chondrocyte PI-3 kinase-Akt signaling pathway is stimulus dependent.
abstract: 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.
  
  
  METHODS
  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.
authors: Department of Internal Medicine, Section on Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA; Thurston Arthritis Research Center, University of North Carolina, Chapel Hill, NC, USA.
authors: M A
authors: MA
authors: Greene
authors: Department of Internal Medicine, Section on Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA; Thurston Arthritis Research Center, University of North Carolina, Chapel Hill, NC, USA. Electronic address: richard_loeser@med.unc.edu.
authors: R F
authors: RF
authors: Loeser
mesh_terms: D002358:Cartilage, Articular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology; D007527:Isoenzymes / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D053509:Matrix Metalloproteinase 13 / Q000096:biosynthesis; D053683:Oncostatin M / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D053583:Interleukin-1beta; D007527:Isoenzymes; D053683:Oncostatin M; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D053509:Matrix Metalloproteinase 13
keywords: Cell signaling; Chondrocyte; Matrix metalloproteinase-13; PI-3 kinase