title: Heme oxygenase-1 mediates protective effects on inflammatory, catabolic and senescence responses induced by interleukin-1β in osteoarthritic osteoblasts.
abstract: Osteoarthritis (OA) is a chronic degenerative joint disease showing altered bone metabolism. Osteoblasts contribute to the regulation of cartilage metabolism and bone remodeling. We have shown previously that induction of heme oxygenase-1 (HO-1) protects OA cartilage against inflammatory and degradative responses. In this study, we investigated the effects of HO-1 induction on OA osteoblast metabolism. HO-1 was induced with cobalt protoporphyrin IX (CoPP) and by transduction with LV-HO-1. In osteoblasts stimulated with interleukin (IL)-1β, CoPP enhanced mineralization, the expression of a number of markers of osteoblast differentiation such as Runx2, bone morphogenetic protein-2, osteocalcin, and collagen 1A1 and 1A2, as well as the ratio osteoprotegerin/receptor activator of nuclear factor-κB ligand. HO-1 induction significantly reduced the expression of matrix metalloproteinase (MMP)-1, MMP-2 and MMP-3, and the production of pro-inflammatory cytokines such as tumor necrosis factor-α and IL-6 whereas IL-10 levels increased. HO-1 also exerted inhibitory effects on prostaglandin (PG)E(2) production which could be dependent on cyclooxygenase-2 and microsomal PGE synthase-1 down-regulation. The activity of senescence-associated β-galactosidase and the expression of the senescence marker caveolin-1 were significantly decreased after HO-1 induction. The inhibition of nuclear factor-κB activation induced by IL-1β in OA osteoblasts may contribute to some HO-1 effects. Our results have shown that HO-1 decreases the production of relevant inflammatory and catabolic mediators that participate in OA pathophysiology thus eliciting protective effects in OA osteoblasts.
authors.affiliation: Department of Pharmacology, University of Valencia, Burjasot, 46100 Valencia, Spain.
authors.forename: Victoria
authors.initials: V
authors.lastname: Clérigues
authors.forename: Maria Isabel
authors.initials: MI
authors.lastname: Guillén
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Castejón
authors.forename: Francisco
authors.initials: F
authors.lastname: Gomar
authors.forename: Vicente
authors.initials: V
authors.lastname: Mirabet
authors.forename: Maria José
authors.initials: MJ
authors.lastname: Alcaraz
mesh_terms: D000368:Aged; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology*; D005260:Female; D051547:Heme Oxygenase-1 / Q000502:physiology*; D006801:Humans; D018836:Inflammation Mediators / Q000502:physiology*; D053583:Interleukin-1beta / Q000502:physiology*; D008297:Male; D008660:Metabolism / Q000502:physiology; D008875:Middle Aged; D010000:Osteitis / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control; D010003:Osteoarthritis / Q000201:enzymology* / Q000503:physiopathology / Q000517:prevention & control; D010006:Osteoblasts / Q000201:enzymology* / Q000473:pathology
chemical_list: D018836:Inflammation Mediators; D053583:Interleukin-1beta; D051547:Heme Oxygenase-1