Heme oxygenase-1 mediates protective effects on inflammatory, catabolic and senescence responses induced by interleukin-1β in osteoarthritic osteoblasts
Heme oxygenase-1 mediates protective effects on inflammatory, catabolic and senescence responses induced by interleukin-1β in osteoarthritic osteoblasts
复制标题
DOI：
10.1016/j.bcp.2011.11.024
复制
发表时间：
2012-02-01
影响因子：
5.8
通讯作者：
Jose Alcaraz, Maria
中科院分区：
文献类型：
--
作者：
Clerigues, Victoria;Isabel Guillen, Maria;Jose Alcaraz, Maria
骨关节炎（OA）是一种慢性退行性关节疾病，表现为骨代谢改变。成骨细胞参与软骨代谢和骨重建的调节。我们以前已经表明，诱导血红素加氧酶-1（HO-1）保护OA软骨免受炎症和降解反应。在这项研究中，我们研究了HO-1诱导对OA成骨细胞代谢的影响。HO-1用钴原卟啉IX（CoPP）诱导，并通过用LV-HO-1转导。在用白细胞介素（IL）-1 β刺激的成骨细胞中，CoPP增强了矿化，成骨细胞分化的许多标志物的表达，如Runx 2、骨形态发生蛋白-2、骨钙素和胶原1A 1和1A 2，以及骨保护素/核因子-κ B配体的受体激活剂的比例。HO-1诱导显著降低了基质金属蛋白酶（MMP）-1、MMP-2和MMP-3的表达，以及促炎细胞因子如肿瘤坏死因子-α和IL-6的产生，而IL-10水平升高。HO-1还对前列腺素（PG）E-2的产生抑制作用，这可能依赖于环氧合酶-2和微粒体PGE合酶-1的下调。HO-1诱导后，衰老相关β-半乳糖苷酶的活性和衰老标记物小窝蛋白-1的表达显着降低。IL-1 β对OA成骨细胞核因子-κ B活化的抑制可能与HO-1的某些作用有关。我们的研究结果表明，HO-1减少了参与OA病理生理学的相关炎症和分解代谢介质的产生，从而引起OA成骨细胞的保护作用。(C)2011 Elsevier Inc. All rights reserved.
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)-1 beta, 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-kappa B ligand. HO-1 induction significantly reduced the expression of matrix metalloproteinase (MMF)-1, MMP-2 and MMP-3, and the production of pro-inflammatory cytokines such as tumor necrosis factor-alpha 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 beta-galactosidase and the expression of the senescence marker caveolin-1 were significantly decreased after HO-1 induction. The inhibition of nuclear factor-kappa B activation induced by IL-1 beta 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. (C) 2011 Elsevier Inc. All rights reserved.