title: IGF-1 and PDGF-bb suppress IL-1β-induced cartilage degradation through down-regulation of NF-κB signaling: involvement of Src/PI-3K/AKT pathway.
abstract: OBJECTIVE
  Interleukin-1β (IL-1β) is a pro-inflammatory cytokine that plays a key role in the pathogenesis of osteoarthritis (OA). Growth factors (GFs) capable of antagonizing the catabolic actions of cytokines may have therapeutic potential in the treatment of OA. Herein, we investigated the potential synergistic effects of insulin-like growth factor (IGF-1) and platelet-derived growth factor (PDGF-bb) on different mechanisms participating in IL-1β-induced activation of nuclear transcription factor-κB (NF-κB) and apoptosis in chondrocytes.
  
  
  METHODS
  Primary chondrocytes were treated with IL-1β to induce dedifferentiation and co-treated with either IGF-1 or/and PDGF-bb and evaluated by immunoblotting and electron microscopy.
  
  
  RESULTS
  Pretreatment of chondrocytes with IGF-1 or/and PDGF-bb suppressed IL-1β-induced NF-κB activation via inhibition of IκB-α kinase. Inhibition of IκB-α kinase by GFs led to the suppression of IκB-α phosphorylation and degradation, p65 nuclear translocation and NF-κB-regulated gene products involved in inflammation and cartilage degradation (COX-2, MMPs) and apoptosis (caspase-3). GFs or BMS-345541 (specific inhibitor of the IKK) reversed the IL-1β-induced down-regulation of collagen type II, cartilage specific proteoglycans, β1-integrin, Shc, activated MAPKinase, Sox-9 and up-regulation of active caspase-3. Furthermore, the inhibitory effects of IGF-1 or/and PDGF-bb on IL-1β-induced NF-κB activation were sensitive to inhibitors of Src (PP1), PI-3K (wortmannin) and Akt (SH-5), suggesting that the pathway consisting of non-receptor tyrosine kinase (Src), phosphatidylinositol 3-kinase and protein kinase B must be involved in IL-1β signaling.
  
  
  CONCLUSIONS
  The results presented suggest that IGF-1 and PDGF-bb are potent inhibitors of IL-1β-mediated activation of NF-κB and apoptosis in chondrocytes, may be mediated in part through suppression of Src/PI-3K/AKT pathway, which may contribute to their anti-inflammatory effects.
authors.affiliation: Department of Anatomical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
authors.forename: Azadeh
authors.initials: A
authors.lastname: Montaseri
authors.forename: Franziska
authors.initials: F
authors.lastname: Busch
authors.forename: Ali
authors.initials: A
authors.lastname: Mobasheri
authors.forename: Constanze
authors.initials: C
authors.lastname: Buhrmann
authors.forename: Constance
authors.initials: C
authors.lastname: Aldinger
authors.forename: Jafar Soleimani
authors.initials: JS
authors.lastname: Rad
authors.forename: Mehdi
authors.initials: M
authors.lastname: Shakibaei
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D000077214:Becaplermin; D002356:Cartilage / Q000187:drug effects / Q000201:enzymology / Q000473:pathology* / Q000648:ultrastructure; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects / Q000201:enzymology / Q000473:pathology / Q000648:ultrastructure; D024043:Collagen Type II / Q000378:metabolism; D004285:Dogs; D015536:Down-Regulation / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D019012:Integrin beta1 / Q000378:metabolism; D053583:Interleukin-1beta / Q000494:pharmacology*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis / Q000494:pharmacology*; D011810:Quinoxalines / Q000494:pharmacology; D055758:SOX9 Transcription Factor / Q000378:metabolism; D055765:Shc Signaling Adaptor Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: C471109:4(2'-aminoethyl)amino-1,8-dimethylimidazo(1,2-a)quinoxaline; D024043:Collagen Type II; D020672:I-kappa B Proteins; D007093:Imidazoles; D019012:Integrin beta1; D053583:Interleukin-1beta; D016328:NF-kappa B; D020574:Proto-Oncogene Proteins c-sis; D011810:Quinoxalines; D055758:SOX9 Transcription Factor; D055765:Shc Signaling Adaptor Proteins; D000072000:NF-KappaB Inhibitor alpha; D000077214:Becaplermin; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases