Upregulation of Heme Oxygenase-1 Inhibits the Maturation and Mineralization of Osteoblasts
Upregulation of Heme Oxygenase-1 Inhibits the Maturation and Mineralization of Osteoblasts
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DOI：
10.1002/jcp.22008
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发表时间：
2010-03-01
影响因子：
5.6
通讯作者：
Yang, Rong-Sen
中科院分区：
文献类型：
--
作者：
Lin, Tzu-Hung;Tang, Chih-Hsin;Yang, Rong-Sen
血红素加氧酶-1 （HO-1）是一种参与血管疾病、移植和炎症的重要酶，它催化血红素降解为一氧化碳和胆绿素。据报道，过表达HO-1可抑制破骨细胞的生成。然而，HO-1对成骨细胞分化的影响尚不清楚。本实验采用表达重组人HO-1和HO-1诱导剂血红素的腺病毒载体，研究HO-1在原代培养成骨细胞中的作用。结果表明，HO-1的诱导抑制了成骨细胞的成熟，包括矿化骨结节形成、碱性磷酸酶活性和碱性磷酸酶、骨钙素和RUNX2等几种分化标志物mRNA表达的降低。此外，HO-1的下游产物胆红素、一氧化碳和铁也参与了HO-1的抑制作用。在成骨细胞和stz诱导的糖尿病小鼠中，H2O2、脂多糖和炎性细胞因子如tnf - α和il -1 β均可诱导HO-1。此外，外源性PPAR γ配体15-deoxy(-Delta 12,14)-prostaglandin-J2 （15d-PGJ2）通过PI3K-Akt和MAPK途径显著提高成骨细胞HO-1 mRNA和蛋白水平。ZnPP IX阻断HO活性可拮抗hemin和15d-PGJ2对骨钙素表达的抑制作用。我们的研究结果表明，HO-1的上调抑制成骨细胞的成熟，HO-1可能参与氧化或炎症诱导的骨质流失。j .细胞。中国生物医学工程学报，2009,31(2):557 - 568。(C) 2009 Wiley-Liss, Inc。
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-alpha and IL-I beta in osteoblasts and also in STZ-induced diabetic mice. In addition, enclogenous PPAR gamma ligand, 15-deoxy(-Delta 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 oxiclative- or inflammation-induced bone loss. J. Cell. Physiol. 222: 757-768, 2010. (C) 2009 Wiley-Liss, Inc.