Heme oxygenase-1 mediates protective effects on inflammatory, catabolic and senescence responses induced by interleukin-1β in osteoarthritic osteoblasts

• Published in: Biochemical pharmacology 2012-02, Vol.83 (3), p.395-405
• Main Authors: Clérigues, Victoria, Guillén, Maria Isabel, Castejón, Miguel Angel, Gomar, Francisco, Mirabet, Vicente, Alcaraz, Maria José
• Format: Article
• Language: English
• Subjects: Aged; beta -Galactosidase; bone metabolism; Bone morphogenetic protein 2; Bone remodelling; Bone turnover; cartilage; Cartilage diseases; caveolin-1; Cbfa-1 protein; Cells, Cultured; Cellular Senescence - physiology; Chromium; Cobalt; Collagen; Cyclooxygenase-2; Cytokines; Female; Gelatinase A; heme oxygenase (biliverdin-producing); Heme oxygenase (decyclizing); Heme oxygenase-1; Heme Oxygenase-1 - physiology; Humans; Inflammation; Inflammation Mediators - physiology; Interleukin 1; Interleukin 10; Interleukin 6; Interleukin-1beta - physiology; Joint diseases; Male; Matrix metalloproteinase; Metabolism; Metabolism - physiology; Middle Aged; Mineralization; necrosis; Osteitis - enzymology; Osteitis - pathology; Osteitis - prevention & control; Osteoarthritis; Osteoarthritis - enzymology; Osteoarthritis - physiopathology; Osteoarthritis - prevention & control; Osteoblastogenesis; Osteoblasts; Osteoblasts - enzymology; Osteoblasts - pathology; Osteocalcin; Osteoprotegerin; pathophysiology; pharmacology; Prostaglandin E; prostaglandin synthase; Prostaglandins; protective effect; protoporphyrin; Senescence; Tumor necrosis factor- alpha
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2011.11.024

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.