Critical role of MKP-1 in lipopolysaccharide-induced osteoclast formation through CXCL1 and CXCL2.
Critical role of MKP-1 in lipopolysaccharide-induced osteoclast formation through CXCL1 and CXCL2.
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DOI：
10.1016/j.cyto.2014.08.007
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发表时间：
2015-01
期刊：
影响因子：
3.8
通讯作者：
Kirkwood, Keith L.
中科院分区：
文献类型：
--
作者：
Valerio, Michael S.;Herbert, Bethany A.;Basilakos, Dimitrios S.;Browne, Courtney;Yu, Hong;Kirkwood, Keith L.
破骨细胞（OC）祖细胞（OCP）在骨髓（BM）中被定义为CD 3 − CD 45 R（B220）− GR 1 − CD 11blo/− CD 115+（dOCP），最近在外周血（PB）中被定义为Lym− Ly 6 G − CD 11b + Ly 6C+。这些祖细胞响应刺激，包括来自周围病原性伴放线菌聚集杆菌的LPS，激活MAPK信号传导，导致细胞因子/趋化因子介导的破骨细胞生成。细胞内负信号通路，包括MAPK磷酸酶-1（MKP-1，基因Dusp 1）使MAPK通路（p-p38和p-JNK）失活并减少炎性细胞因子/趋化因子。使用确定的OC祖细胞群体描述MKP-1在趋化因子介导的OC形成中的作用。鉴于其在先天免疫炎症信号传导中的作用，我们假设MKP-1通过去调节趋化因子调节LPS诱导的BM OCP形成OC。获得WT和Dusp 1 −/−雌性小鼠（8- 12周）的BM和PB，并将其分选到定义的祖细胞群中。用MCSF和RANKL引发BM分选的dOCP（48小时），用媒介物或趋化因子阻断抗体阻断并用LPS刺激（48- 96小时）。TRAP测定和OC活性测量处理后的OC形成和活性。Nanostring Array和qPCR用于基因表达分析。与匹配的WT相比，Dusp 1 −/− dOCP从CD 11bhi和dOCP形成更多和更大的破骨细胞（P<0.05）。与WT对照组相比，PB衍生的dOCP从Dusp 1 −/−小鼠中产生了更大、功能更强的破骨细胞。Nanostring阵列数据显示Dusp 1 −/−与WT细胞相比，趋化因子表达显著失调。靶基因的qPCR验证显示，与WT相比，Dusp 1缺陷型CD 11b+群体在CD 11bhi和dOCP中显示出1.5-3.5倍的CXCL 1表达和2-3倍的CXCL 2表达（各P<0.05）。使用抗CXCL 1和CXCL 2抗体的抗体阻断研究减弱了Dusp 1 −/−细胞中的破骨细胞生成。MKP-1负调节趋化因子驱动的OC形成和随后的骨吸收响应于LPS刺激。总的来说，这些数据提供了有用的洞察机制可能导致牙周病的治疗治疗的发展。
Osteoclast (OC) progenitors (OCP) have been defined in the bone marrow (BM) as CD3−CD45R(B220)−GR1−CD11blo/−CD115+ (dOCP) and more recently in the peripheral blood (PB) as Lym−Ly6G−CD11b+Ly6C+. These progenitors respond to stimuli, including LPS from periopathogenic Aggregatibacter actinomycetemcomitans, activating MAPK signaling, resulting in cytokine/chemokine-mediated osteoclastogenesis. Intracellular negative signaling pathways, including MAPK phosphatase-1 (MKP-1, gene Dusp1) deactivate MAPK pathways (p-p38 and p-JNK) and reduce inflammatory cytokines/chemokines. To delineate the role of MKP-1 in chemokine-mediated OC formation using defined OC progenitor populations. Given its role in innate immune inflammatory signaling, we hypothesize that MKP-1 regulates LPS-induced OC formation from BM OCP through deregulated chemokines. BM and PB from WT and Dusp1−/− female mice (8–12wks) was obtained and sorted into defined progenitor populations. BM sorted dOCP were primed with MCSF and RANKL (48hrs), blocked with vehicle or chemokine blocking antibodies and stimulated with LPS (48–96hrs). TRAP assay and OC activity were measured for OC formation and activity following treatments. Nanostring Array and qPCR were utilized for gene expression analysis. Dusp1−/− dOCPs formed more and larger osteoclasts from CD11bhi and dOCP compared to matched WT (P<0.05 each). PB-derived dOCP produced larger and more functional osteoclasts from Dusp1−/− mice compared to WT controls. Nanostring array data revealed significant deregulation in chemokine expression from Dusp1−/− vs. WT cells. qPCR validation of target genes revealed that Dusp1 deficient CD11b+ populations display 1.5–3.5-fold greater expression of CXCL1 and 2–3-fold greater expression of CXCL2 compared to WT in CD11bhi and dOCP (P<0.05 each). Antibody blocking studies using anti-CXCL1 and CXCL2 antibodies blunted osteoclastogenesis in Dusp1−/− cells. MKP-1 negatively regulates chemokine-driven OC formation and subsequent bone resorption in response to LPS stimulation. Collectively, these data provide useful insight into mechanisms potentially leading to the development of therapeutic treatment of periodontal disease.
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影响因子：
7.6
作者：
Xing, Q.;de Vos, P.;Ren, Y.
通讯作者：
Ren, Y.
DOI：
10.1084/jem.20051753
发表时间：
2006-01-23
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Hammer M;Mages J;Dietrich H;Servatius A;Howells N;Cato AC;Lang R
通讯作者：
Lang R
影响因子：
6.2
作者：
Jacome-Galarza, Christian E.;Lee, Sun-Kyeong;Lorenzo, Joseph A.;Aguila, Hector Leonardo
通讯作者：
Aguila, Hector Leonardo
DOI：
10.1155/2012/308943
发表时间：
2012
期刊：
Journal of signal transduction
影响因子：
--
作者：
Li Q;Valerio MS;Kirkwood KL
通讯作者：
Kirkwood KL
影响因子：
3.8
作者：
Ha, Jeongim;Lee, Youngkyun;Kim, Hong-Hee
通讯作者：
Kim, Hong-Hee