Osteopontin Has a Crucial Role in Osteoclast-Like Multinucleated Giant Cell Formation
Osteopontin Has a Crucial Role in Osteoclast-Like Multinucleated Giant Cell Formation
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DOI：
10.1002/jcb.24695
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发表时间：
2014-03-01
影响因子：
4
通讯作者：
Morimoto, Akira
中科院分区：
文献类型：
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作者：
Oh, Yukiko;Oh, Iekuni;Morimoto, Akira
破骨细胞（OC）是炎性骨疾病如类风湿性关节炎和朗格汉斯细胞组织细胞增生症的致病性骨破坏的主要参与者。最近，研究表明，未成熟树突状细胞（iDC）融合更快，更有效地比单核细胞形成OC样多核巨细胞（MGCs），骨桥蛋白（OPN）参与炎症性骨疾病的发病机制。在这项研究中，我们假设OPN是从iDC产生OC样MGCs的关键因素。我们使用体外培养系统将来源于从健康供体的血液获得的单核细胞的iDC分化为OC样MGCs。我们评估了分化过程中OPN水平和OPN受体的表达。OPN具有精氨酸-甘氨酸-天冬氨酸（RGD）基序，蛋白酶切割显示SVVYGLR基序。在OC样MGC形成过程中，全长和切割形式的OPN浓度均增加。OPN RGD和SVVYGLR识别受体的表达也在后期增加。我们分析了阻断OPN与其受体的结合是否会影响OC样MGC的形成。用OPN siRNA处理的单核细胞能够有效地分化成iDC;然而，这些iDC分化成OC样MGCs显著减少。RGD合成肽对OC样MGCs的形成无明显抑制作用。相比之下，SVVYGLR合成肽引起的显著降低。这些数据表明，OPN的裂解形式在分化的早期阶段以自分泌和/或旁分泌方式驱动iDC分化为OC样MGCs中起关键作用。J.细胞。115：585-595，2014. (c)2013 Wiley Periodicals，Inc.
The osteoclast (OC) is a major player in the pathogenic bone destruction of inflammatory bone diseases such as rheumatoid arthritis and Langerhans cell histiocytosis. Recently, it was shown that immature dendritic cells (iDC) fuse faster and more efficiently than monocytes in forming OC-like multinucleated giant cells (MGCs), and that osteopontin (OPN) is involved in the pathogenesis of inflammatory bone diseases. In this study, we hypothesized that OPN is a key factor for generation of OC-like MGCs from iDCs. We used an in vitro culture system to differentiate iDCs, derived from monocytes obtained from the blood of healthy donors, into OC-like MGCs. We evaluated OPN levels and expression of OPN receptors during the course of differentiation. OPN has an arginine-glycine-aspartic acid (RGD) motif, and protease cleavage reveals a SVVYGLR motif. The concentrations of both full-length and cleaved forms of OPN increased during the course of OC-like MGC formation. Expression of OPN RGD- and SVVYGLR-recognizing receptors also increased at later stages. We analyzed whether blocking OPN binding to its receptors affected OC-like MGC formation. Monocytes treated with OPN siRNA were able to differentiate into iDCs effectively; however, differentiation of these iDCs into OC-like MGCs was significantly reduced. The formation of OC-like MGCs was not significantly reduced by RGD synthetic peptide. By contrast, SVVYGLR synthetic peptide caused a significant reduction. These data suggest that the cleaved form of OPN plays a critical role in driving iDC differentiation into OC-like MGCs in the early phase of differentiation, in an autocrine and/or paracrine fashion. J. Cell. Biochem. 115: 585-595, 2014. (c) 2013 Wiley Periodicals, Inc.