Heme oxygenase 1 (HO-1) regulates osteoclastogenesis and bone resorption.
Heme oxygenase 1 (HO-1) plays an important role in vascular disease, transplantation, and inflammation. In animal models of acute and chronic inflammation, induction of HO-1 has anti-inflammatory and cytoprotective properties. Since inflammation is an important trigger of osteoclastogenesis, we hypothesized that HO-1 might influence osteoclastogenesis. We investigated the effects of induction of HO-1 on osteoclast formation in vitro and in vivo. Furthermore, we addressed the role of HO-1 in inflammatory bone loss in humans. When HO-1 was induced by hemin in vitro, a significant dose-dependent inhibition of osteoclastogenesis was observed. Up-regulation of HO-1 was mediated by activation of MAPK and primarily prevented differentiation of osteoclast precursors to osteoclasts, whereas it did not affect mature osteoclasts. Anti-osteoclastogenic properties of hemin were based on a down-regulation of c-fms, RANK, TRAF-6, and c-fos. In addition, induction of HO-1 inhibited TNF-triggered osteoclast differentiation in vitro as well as LPS-driven inflammatory bone loss in vivo. Furthermore, HO-1 induction suppressed osteoclastogenesis and bone destruction in a TNF-mediated arthritis. In line, assessment of synovial tissue from rheumatoid arthritis patients revealed that osteoclasts are usually HO-1 negative. Moreover, serum levels of bilirubin, a metabolite of HO-1, were elevated in rheumatoid arthritis patients without bone damage, suggesting HO-1 affects bone loss in humans. In summary, these data indicate that HO-1 negatively regulates osteoclastogenesis, leading to a positive net balance of bone.
Zwerina
Jochen
J
Division of Rheumatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
Tzima
Sotiria
S
Hayer
Silvia
S
Redlich
Kurt
K
Hoffmann
Oskar
O
Hanslik-Schnabel
Beatrice
B
Smolen
Josef S
JS
Kollias
George
G
Schett
Georg
G
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001172:Arthritis, Rheumatoid / Q000378:metabolism / Q000628:therapy; D001663:Bilirubin / Q000378:metabolism; D001862:Bone Resorption; D001842:Bone and Bones / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004789:Enzyme Activation; D006023:Glycoproteins / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000737:chemistry* / Q000378:metabolism; D006427:Hemin / Q000737:chemistry; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation; D008070:Lipopolysaccharides / Q000737:chemistry; D051379:Mice; D008954:Models, Biological; D010010:Osteoclasts / Q000166:cytology* / Q000378:metabolism; D053244:Osteoprotegerin; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D013154:Spleen / Q000378:metabolism; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D015854:Up-Regulation
D000893:Anti-Inflammatory Agents; D006023:Glycoproteins; D008070:Lipopolysaccharides; D053244:Osteoprotegerin; D016760:Proto-Oncogene Proteins c-fos; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; D048029:TNF Receptor-Associated Factor 6; C506030:TNFRSF11B protein, human; C506031:Tnfrsf11b protein, mouse; D006427:Hemin; D051547:Heme Oxygenase-1; D016186:Receptor, Macrophage Colony-Stimulating Factor; D001663:Bilirubin