Celastrol attenuates bone erosion in collagen-Induced arthritis mice and inhibits osteoclast differentiation and function in RANKL-induced RAW264.7
Celastrol attenuates bone erosion in collagen-Induced arthritis mice and inhibits osteoclast differentiation and function in RANKL-induced RAW264.7
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Celastrol 可减轻胶原诱导的关节炎小鼠的骨侵蚀，并抑制 RANKL 诱导的 RAW264.7 中的破骨细胞分化和功能。
DOI：
10.1016/j.intimp.2014.12.012
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发表时间：
2015-02-01
影响因子：
5.6
通讯作者：
Tan, Wenfeng
中科院分区：
文献类型：
--
作者：
Gan, Ke;Xu, Lingxiao;Tan, Wenfeng
近年来，雷公藤（Tripterygium wilfordii Hook f，TwHF）因其在类风湿性关节炎（RA）治疗中的潜在应用而受到越来越多的关注。人们普遍认为雷公藤具有抗风湿活性，主要取决于其有效的抗炎特性。为了进一步探索明确的TwHF衍生的单一化合物雷公藤红素在RA中的治疗潜力，我们研究了雷公藤红素对胶原诱导的关节炎（CIA）小鼠骨侵蚀的治疗功效，并描述了其对RANKL诱导的成骨细胞前体RAW 264. 7细胞系中成骨细胞分化和功能的影响。在CIA小鼠中，每天注射雷公藤红素（在关节炎诱导后第28天开始）显著抑制关节炎，并减少关节中的骨损伤，如通过组织学和骨微计算机断层扫描（Cr）所证明的。这些作用伴随着关节中破骨细胞、血清抗酒石酸酸性磷酸酶（TRAP）5 b以及骨诱导基因（Trap、Ctsk、Ctr、Mmp-9）和转录因子（c-Fos、c-Jun和NFATc 1）表达的减少。当RAW264.7细胞用RANKL处理时，雷公藤红素以剂量依赖性方式抑制TRAP +多核细胞的形成和骨吸收活性。此外，雷公藤红素降低RANKL诱导的骨调节基因和转录因子的表达，以及NF-κ B和丝裂原活化蛋白激酶（MAPK）的磷酸化。这些发现表明雷公藤红素可以直接抑制成骨细胞的形成和功能，提示雷公藤红素用于管理RA，特别是预防骨破坏的新的治疗策略。(C)2014爱思唯尔有限公司版权所有。
Recently, the traditional Chinese medicine Tripterygium wilfordii Hook f (TwHF) of the Celastraceae family has attracted increasing attention for its potential therapeutic application in patients with rheumatoid arthritis (RA). It is well accepted that TwHF exerts the antirheumatic activity and mainly depends on its potent anti-inflammatory property. To further explore the therapeutic potential of the well-defined TwHF-derived single compound celastrol in RA, we study the therapeutic efficacy of celastrol on bone erosion in collagen-induced arthritis (CIA) mice and delineate its effects on osteodast differentiation and functions in RANKL-induced osteodast precursors RAW264.7 cell line. In CIA mice, daily injection of celastrol (beginning on day 28 after arthritis induction) markedly suppressed arthritis, and reduced bone damage in the joints as demonstrated by histology and bone micro-computed tomography (Cr). The effects were accompanied by reductions of osteoclast cells in joints, serum tartrate-resistant acid phosphatase (TRAP) 5b, and expression of osteoclastic genes (Trap, Ctsk, Ctr, Mmp-9) and transcriptional factors (c-Fos, c-Jun and NFATc1). When RAW264.7 cells were treated with RANKL, celastrol inhibited the formation of TRAP + multinucleated cells and the bone-resorbing activity in dose-dependent manners. Furthermore, celastrol reduced the RANKL-induced expression of osteodastic genes and transcriptional factors, as well as phosphorylation of NF-kB and mitogen-activated protein kinases (MAPK). These findings show that celastrol could directly inhibit osteodast formation and function, suggesting a novel therapeutic strategy of celastrol for managing RA, especially in preventing bone destruction. (C) 2014 Elsevier B.V. All rights reserved.