Activation of the Peroxisome Proliferator-Activated Receptor γ Coactivator 1β/NFATc1 Pathway in Circulating Osteoclast Precursors Associated With Bone Destruction in Rheumatoid Arthritis
Activation of the Peroxisome Proliferator-Activated Receptor γ Coactivator 1β/NFATc1 Pathway in Circulating Osteoclast Precursors Associated With Bone Destruction in Rheumatoid Arthritis
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与类风湿关节炎骨破坏相关的循环破骨细胞前体中过氧化物酶体增殖物激活受体 γ 共激活剂 1 beta/NFATc1 通路的激活
DOI：
10.1002/art.40868
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发表时间：
2019-08-01
影响因子：
13.3
通讯作者：
Dai, Lie
中科院分区：
文献类型：
--
作者：
Ma, Jian-Da;Jing, Jun;Dai, Lie
目的研究类风湿关节炎（RA）骨部位破骨细胞的激活。循环破骨细胞前体的作用机制尚不清楚。在小鼠模型中，过氧化物酶体增殖物激活受体γ辅助激活因子1 β (PGC-1 β)参与破骨细胞发生的转录调控。本研究旨在探讨PGC-1 β对循环破骨细胞前体的贡献及其与RA骨破坏的联系。方法PGC-1 β在RA外周血CD14+单核细胞中的表达升高，并与关节破坏相关。用PGC-1 β基因沉默或过表达的慢病毒载体转染RA患者或健康对照细胞，并用巨噬细胞集落刺激因子和RANKL培养。在这些成熟破骨细胞中测量骨吸收活性、骨降解酶和信号分子。结果RA外周血CD14+单核细胞PGC-1 β核积累增加，且破骨细胞生成能力强于健康对照组。PGC-1 β蛋白表达与x线关节破坏呈正相关（r = 0.396 ~ 0.413，均P < 0.05）。PGC-1 β敲除抑制组织蛋白酶K、抗酒石酸酸性磷酸酶（TRAP）和基质金属蛋白酶9 （MMP-9）的表达（减少51-82%），以及破骨细胞分化和骨吸收活性。相反，PGC-1 β过表达增加了这些标记物（1.5-1.8倍）和破骨细胞的发生。VIVIT是一种NFATc1激活抑制剂，通过降低组织蛋白酶K、TRAP和MMP-9的表达来抑制过表达PGC-1 β的作用。染色质免疫沉淀试验和双荧光素酶报告基因试验显示PGC-1 β与NFATc1启动子结合，导致转录激活。结论循环破骨细胞前体PGC-1 β /NFATc1通路的激活与RA的骨破坏有关。这可能是一个新的治疗目标。
Objective Activation of osteoclastogenesis at the bone site in rheumatoid arthritis (RA) is well established. The mechanisms by which circulating osteoclast precursors contribute are still unclear. Peroxisome proliferator-activated receptor gamma coactivator 1 beta (PGC-1 beta) is implicated in transcriptional regulation of osteoclastogenesis in mouse models. This study was undertaken to investigate the contribution of PGC-1 beta to circulating osteoclast precursors and its link to bone destruction in RA. Methods PGC-1 beta expression in RA peripheral blood CD14+ monocytes was increased and showed correlation with joint destruction shown on radiographs. Cells from RA patients or healthy controls were transfected with a lentivirus vector for PGC-1 beta gene silencing or overexpression and cultured with macrophage colony-stimulating factor and RANKL. Bone resorption activity, bone-degrading enzymes, and signaling molecules were measured in these mature osteoclasts. Results Increased nuclear accumulation of PGC-1 beta was observed in RA peripheral blood CD14+ monocytes, and these cells had stronger osteoclastogenesis than in healthy controls. PGC-1 beta protein expression was positively correlated with radiographic joint destruction (r = 0.396-0.413; all P < 0.05). PGC-1 beta knockdown suppressed (51-82% reduction) the expression of cathepsin K, tartrate-resistant acid phosphatase (TRAP), and matrix metalloproteinase 9 (MMP-9), as well as osteoclast differentiation and bone resorption activity. Conversely, PGC-1 beta overexpression increased these markers (by 1.5-1.8-fold) and osteoclastogenesis. VIVIT, an inhibitor of NFATc1 activation, inhibited the effect of overexpressed PGC-1 beta by reducing cathepsin K, TRAP, and MMP-9 expression. Chromatin immunoprecipitation assay and dual-luciferase reporter gene assay showed PGC-1 beta bound to NFATc1 promoter, leading to transcriptional activation. Conclusion Activation of the PGC-1 beta/NFATc1 pathway in circulating osteoclast precursors was associated with bone destruction in RA. This may represent a new treatment target.