Heme oxygenase 1 (HO‐1) regulates osteoclastogenesis and bone resorption

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Abstract
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.
Funding Information
  • Austrian Science Fund

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