Acute phase serum amyloid A induces proinflammatory cytokines and mineralization via toll-like receptor 4 in mesenchymal stem cells
Acute phase serum amyloid A induces proinflammatory cytokines and mineralization via toll-like receptor 4 in mesenchymal stem cells
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DOI：
10.1016/j.scr.2015.06.008
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发表时间：
2015-07-01
影响因子：
1.2
通讯作者：
Jakob, Franz
中科院分区：
文献类型：
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作者：
Ebert, Regina;Benisch, Peggy;Jakob, Franz
本研究分析了血清淀粉样蛋白A（SAA）在人骨髓间充质干细胞（hMSCs）及其成骨后代中的作用，重点是衰老、分化和矿化。SAA是Toll样受体的配体。体外老化的hMSC形成衰老相关分泌表型（SASP），导致在进入复制性衰老之前增强的SAA 1/2、TLR 2/4和促炎细胞因子（IL 6、IL 8、IL 1 β、CXCL 1、CXCL 2）表达。重组人SAA 1（rhSAA 1）诱导MSC中SASP相关基因和蛋白的表达，而TLR 4抑制剂CLI-095可阻断rhSAA 1诱导的SASP相关基因和蛋白表达。在诱导成骨分化时刺激了相同模式的SASP类似基因，这伴随着自分泌SAA 1/2表达。在这种情况下，额外的rhSAA 1增强了SASP样表型，加速了成骨分化的促炎阶段，并增强了矿化。自分泌/旁分泌和rhSAA 1通过TLR 4刺激促炎表型，这是成骨分化和衰老发展的早期阶段的一部分。这种信号级联反应与骨形成和矿化密切相关，但也可能传播病理性骨外钙化状况，如钙化炎症和动脉粥样硬化。(C)2015作者由爱思唯尔公司出版
The role of serum amyloid A (SAA) proteins, which are ligands for toll-like receptors, was analyzed in human bone marrow-derived mesenchymal stem cells (hMSCs) and their osteogenic offspring with a focus on senescence, differentiation andmineralization. In vitro aged hMSC developed a senescence-associated secretory phenotype (SASP), resulting in enhanced SAA1/2, TLR2/4 and proinflammatory cytokine (IL6, IL8, IL1 beta, CXCL1, CXCL2) expression before entering replicative senescence. Recombinant human SAA1 (rhSAA1) induced SASP-related genes and proteins in MSC, which could be abolished by cotreatment with the TLR4-inhibitor CLI-095. The same pattern of SASP-resembling genes was stimulated upon induction of osteogenic differentiation, which is accompanied by autocrine SAA1/2 expression. In this context additional rhSAA1 enhanced the SASP-like phenotype, accelerated the proinflammatory phase of osteogenic differentiation and enhanced mineralization. Autocrine/paracrine and rhSAA1 via TLR4 stimulate a proinflammatory phenotype that is both part of the early phase of osteogenic differentiation and the development of senescence. This signaling cascade is tightly involved in bone formation and mineralization, but may also propagate pathological extraosseous calcification conditions such as calcifying inflammation and atherosclerosis. (C) 2015 The Authors. Published by Elsevier B.V.