Upregulation of heme oxygenase-1 inhibits the maturation and mineralization of osteoblasts
Journal
Journal of Cellular Physiology
Journal Volume
222
Journal Issue
3
Pages
757-768
Date Issued
2010
Author(s)
Abstract
Heme-oxygenase-1 (HO-1), an important enzyme involved in vascular disease, transplantation, and inflammation, catalyzes the degradation of heme into carbon monoxide and biliverdin. It has been reported that overexpression of HO-1 inhibits osteoclastogenesis. However, the effect of HO-1 on osteoblast differentiation is still not clear. We here used adenoviral vector expressing recombinant human HO-1 and HO-1 inducer hemin to study the effects of HO-1 in primary cultured osteoblasts. The results showed that induction of HO-1 inhibited the maturation of osteoblasts including mineralized bone nodule formation, alkaline phosphatase activity and decreased mRNA expression of several differentiation markers such as alkaline phosphatase, osteocalcin, and RUNX2. Furthermore, downstream products of HO-1, bilirubin, carbon monoxide, and iron, are involved in the inhibitory action of HO-1. HO-1 can be induced by H2O2, lipopolysaccharide and inflammatory cytokines such as TNF-α and IL-1β in osteoblasts and also in STZ-induced diabetic mice. In addition, endogenous PPARγ ligand, 15-deoxy-Δ 12,14-prostaglandin-J2 (15d-PGJ2) markedly increased both mRNA and protein levels of HO-1 in osteoblasts via PI3K-Akt and MAPK pathways. Blockade of HO activity by ZnPP IX antagonized the inhibitory action on osteocalcin expression by hemin and 15d-PGJ2. Our results indicate that upregulation of HO-1 inhibits the maturation of osteoblasts and HO-1 may be involved in oxidative- or inflammation-induced bone loss. ? 2009 Wiley-Liss, Inc.
Other Subjects
15 deoxy delta12,14 prostaglandin J2; adenovirus vector; alkaline phosphatase; bilirubin; carbon monoxide; heme oxygenase; heme oxygenase 1; hemin; hydrogen peroxide; interleukin 1beta; iron; lipopolysaccharide; messenger RNA; mitogen activated protein kinase; osteocalcin; phosphatidylinositol 3 kinase; protein kinase B; protoporphyrin zinc; transcription factor RUNX2; tumor necrosis factor alpha; unclassified drug; zinc protoporphyrin IX; animal cell; animal experiment; animal model; animal tissue; article; bone maturation; bone mineralization; cell culture; cell maturation; controlled study; drug effect; drug inhibition; drug mechanism; enzyme activity; fetus; inflammation; male; mouse; nonhuman; ossification; osteoblast; osteolysis; oxidation; priority journal; protein expression; rat; streptozocin diabetes; upregulation; 1-Phosphatidylinositol 3-Kinase; Alkaline Phosphatase; Animals; Bilirubin; Calcification, Physiologic; Carbon Dioxide; Cell Differentiation; Cells, Cultured; Core Binding Factor Alpha 1 Subunit; Cytokines; Diabetes Mellitus, Experimental; Heme Oxygenase (Decyclizing); Heme Oxygenase-1; Hemin; Humans; Hydrogen Peroxide; Inflammation Mediators; Iron; Lipopolysaccharides; Male; Membrane Proteins; Mice; Mice, Inbred ICR; Mitogen-Activated Protein Kinases; Organometallic Compounds; Osteoblasts; Osteocalcin; Oxidative Stress; Prostaglandin D2; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; RNA, Messenger; Signal Transduction; Time Factors; Transduction, Genetic; Up-Regulation; Mus
Type
journal article