TLR signaling that induces weak inflammatory response and SHIP1 enhances osteogenic functions.
TLR signaling that induces weak inflammatory response and SHIP1 enhances osteogenic functions.
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DOI：
10.1038/boneres.2014.31
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发表时间：
2014
期刊：
影响因子：
12.7
通讯作者：
Darveau, Richard P.
中科院分区：
文献类型：
--
作者：
Muthukuru, Manoj;Darveau, Richard P.
Toll样受体(TLR)介导的炎症反应可对骨代谢产生负面影响。在这项研究中，我们确定了在TLR信号下游的炎症反应中成骨是如何被调节的。人原代成骨细胞在胶原凝胶中培养。分别用Pam3CSK4(P3C)和大肠杆菌脂多糖(EcLPS)作为TLR2和TLR4配体。用具有TLR4激动剂(Pg1690)和TLR4拮抗剂(Pg1449)TLR2活性的牙龈卟啉单胞菌(Pg1690)和突变型大肠杆菌(LPxE/LPxF/WSK)。分析了在成骨、碱性磷酸酶和矿化过程中具有调节作用的IL-1、β和含SH2的肌醇磷酸酶-1。3用α-氨基胆烷(3AC)抑制SHIP1。我们的结果表明，P3C刺激的成骨细胞不能诱导IL-1β，但能强烈上调SHIP1，增强成骨介质。相反，ECLPS可显著诱导IL-1β，但不能诱导成骨介质。而Pg1690下调成骨介质，Pg1449增强成骨反应，提示TLR4信号即使具有TLR2活性也使成骨无效。有趣的是，诱导弱炎症的突变型大肠杆菌脂多糖上调了成骨，但SHIP1没有被诱导。此外，抑制SHIP1显著上调TLR2介导的炎症反应并下调成骨。综上所述，这些结果表明，通过TLR2(具有SHIP1活性)和突变型TLR4配体诱导的弱炎症反应可以促进成骨。
Toll-like receptor (TLR)-mediated inflammatory response could negatively affect bone metabolism. In this study, we determined how osteogenesis is regulated during inflammatory responses that are downstream of TLR signaling. Human primary osteoblasts were cultured in collagen gels. Pam3CSK4 (P3C) and Escherichia coli lipopolysaccharide (EcLPS) were used as TLR2 and TLR4 ligand respectively. Porphyromonas gingivalis LPS having TLR2 activity with either TLR4 agonism (Pg1690) or TLR4 antagonism (Pg1449) and mutant E. coli LPS (LPxE/LPxF/WSK) were used. IL-1β, SH2-containing inositol phosphatase-1 (SHIP1) that has regulatory roles in osteogenesis, alkaline phosphatase and mineralization were analyzed. 3α-Aminocholestane (3AC) was used to inhibit SHIP1. Our results suggest that osteoblasts stimulated by P3C, poorly induced IL-1β but strongly upregulated SHIP1 and enhanced osteogenic mediators. On the contrary, EcLPS significantly induced IL-1β and osteogenic mediators were not induced. While Pg1690 downmodulated osteogenic mediators, Pg1449 enhanced osteogenic responses, suggesting that TLR4 signaling annuls osteogenesis even with TLR2 activity. Interestingly, mutant E. coli LPS that induces weak inflammation upregulated osteogenesis, but SHIP1 was not induced. Moreover, inhibiting SHIP1 significantly upregulated TLR2-mediated inflammatory response and downmodulated osteogenesis. In conclusion, these results suggest that induction of weak inflammatory response through TLR2 (with SHIP1 activity) and mutant TLR4 ligands could enhance osteogenesis.
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在间充质基质细胞衍生的骨基因生成剂中，长时间暴露于细菌毒素下调Toll样受体的表达。
影响因子：
--
作者：
Mo, Irene Fung Ying;Yip, Kevin Hak Kong;Chan, Wing Keung;Law, Helen Ka Wai;Lau, Yu Lung;Chan, Godfrey Chi Fung
通讯作者：
Chan, Godfrey Chi Fung
影响因子：
4.8
作者：
Gilbert, L;He, XF;Nanes, MS
通讯作者：
Nanes, MS
影响因子：
56.9
作者：
Mata-Haro, Veronica;Cekic, Caglar;Mitchell, Thomas C.
通讯作者：
Mitchell, Thomas C.
影响因子：
5.5
作者：
Beutler, B;Hoebe, K;Ulevitch, RJ
通讯作者：
Ulevitch, RJ
影响因子：
3.1
作者：
Al-Qutub, Montaser N.;Braham, Pamela H.;Darveau, Richard P.
通讯作者：
Darveau, Richard P.