title: Type II collagen peptide stimulates Akt leading to nuclear factor-κB activation: its inhibition by hyaluronan.
abstract: While nuclear factor (NF)-κB is a critical pathway for matrix metalloproteinase (MMP)-13 induction in chondrocytes, intracellular upstream events for NF-κB activation by the type II collagen peptide (CB12-II) with catabolic activities remain unclear. Hyaluronan (HA) of high molecular weight is clinically used for treatment of osteoarthritis (OA) by intra-articular injection. Although HA can suppress NF-κB activation by CB12-II, it is still obscure how HA affects intracellular upstream pathways leading to NF-κB up-regulation in response to CB12-II. Thus, this study was aimed to investigate the involvement of phosphoinositide-3-OH kinase (PI3K)/Akt in the inhibition of CB12-II-activated NF-κB pathway by HA in OA chondrocytes. In monolayer cultures, pre-treatment with HA of 2700 kDa significantly inhibited MMP-13 production by CB12-II-stimulated chondrocytes. CB12-II activated Akt and NF-κB whereas HA down-regulated CB12-II-stimulated phosphorylation of Akt and NF-κB. Inhibition studies using LY294002 revealed the requirement of PI3K/Akt pathway for CB12-II-stimulated NF-κB activation in association with MMP-13 production.Pretreatment with anti-CD44 antibody reversed the inhibitory effects of HA on CB12-II-induced production of MMP-13 and activation of Akt and NF-κB. Herein, we provided the first evidence that HA suppresses CB12-II-activated PI3K/Akt pathway leading to down-regulation ofNF-κB with diminished MMP-13 production through interaction with CD44.
authors.affiliation: Department of Orthopaedic Surgery, Kobe City Medical Center General Hospital, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yasuda
mesh_terms: D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects* / Q000378:metabolism; D024043:Collagen Type II / Q000737:chemistry / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D006820:Hyaluronic Acid / Q000494:pharmacology; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000819:agonists*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D024043:Collagen Type II; D018960:Hyaluronan Receptors; D016328:NF-kappa B; D010446:Peptide Fragments; D006820:Hyaluronic Acid; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D053509:Matrix Metalloproteinase 13