硬骨素
医学
骨保护素
内分泌学
骨钙素
内科学
骨细胞
成骨细胞
促炎细胞因子
骨重建
骨吸收
破骨细胞
炎症
Wnt信号通路
细胞生物学
化学
碱性磷酸酶
生物
体外
信号转导
受体
酶
激活剂(遗传学)
生物化学
作者
Gisela Ruiz Heiland,Karin Zwerina,Wolfgang Baum,Trayana Kireva,Jörg H. W. Distler,Mario Grisanti,Frank Asuncion,Xiadong Li,Michael S. Ominsky,William G. Richards,Georg Schett,Jochen Zwerina
标识
DOI:10.1136/ard.2010.132852
摘要
Introduction Inflammation is a major risk factor for systemic bone loss. Proinflammatory cytokines like tumour necrosis factor (TNF) affect bone homeostasis and induce bone loss. It was hypothesised that impaired bone formation is a key component in inflammatory bone loss and that Dkk-1, a Wnt antagonist, is a strong inhibitor of osteoblast-mediated bone formation. Methods TNF transgenic (hTNFtg) mice were treated with neutralising antibodies against TNF, Dkk-1 or a combination of both agents. Systemic bone architecture was analysed by bone histomorphometry. The expression of β-catenin, osteoprotegerin and osteocalcin was analysed. In vitro, primary osteoblasts were stimulated with TNF and analysed for their metabolic activity and expression of Dkk-1 and sclerostin. Sclerostin expression and osteocyte death upon Dkk-1 blockade were analysed in vivo. Results Neutralisation of Dkk-1 completely protected hTNFtg mice from inflammatory bone loss by preventing TNF-mediated impaired osteoblast function and enhanced osteoclast activity. These findings were accompanied by enhanced skeletal expression of β-catenin, osteocalcin and osteoprotegerin. In vitro, TNF rapidly increased Dkk-1 expression in primary osteoblasts and effectively blocked osteoblast differentiation. Moreover, blockade of Dkk-1 not only rescued impaired osteoblastogenesis but also neutralised TNF-mediated sclerostin expression in fully differentiated osteoblasts in vitro and in vivo. Conclusions These findings indicate that low bone formation and expression of Dkk-1 trigger inflammatory bone loss. Dkk-1 blocks osteoblast differentiation, induces sclerostin expression and leads to osteocyte death. Inhibition of Dkk-1 may thus be considered as a potent strategy to protect bone from inflammatory damage.
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