Gan Ke, Xu Lingxiao, Feng Xiaoke, Zhang Qiande, Wang Fang, Zhang Miaojia, Tan Wenfeng
Department of Rheumatology, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, China; Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China.
Department of Rheumatology, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, China.
Int Immunopharmacol. 2015 Feb;24(2):239-246. doi: 10.1016/j.intimp.2014.12.012. Epub 2014 Dec 19.
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 osteoclast differentiation and functions in RANKL-induced osteoclast 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 (CT). 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 osteoclastic 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 osteoclast formation and function, suggesting a novel therapeutic strategy of celastrol for managing RA, especially in preventing bone destruction.
最近，卫矛科的传统中药雷公藤（TwHF）因其在类风湿关节炎（RA）患者中的潜在治疗应用而受到越来越多的关注。人们普遍认为，雷公藤发挥抗风湿活性主要依赖于其强大的抗炎特性。为了进一步探索雷公藤来源明确的单一化合物——雷公藤红素在类风湿关节炎中的治疗潜力，我们研究了雷公藤红素对胶原诱导性关节炎（CIA）小鼠骨侵蚀的治疗效果，并阐述了其对RANKL诱导的破骨细胞前体RAW264.7细胞系中破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（从关节炎诱导后第28天开始）可显著抑制关节炎，并减少关节中的骨损伤，组织学和骨微计算机断层扫描（CT）均证实了这一点。这些效果伴随着关节中破骨细胞数量的减少、血清抗酒石酸酸性磷酸酶（TRAP）5b以及破骨细胞基因（Trap、Ctsk、Ctr、Mmp - 9）和转录因子（c - Fos、c - Jun和NFATc1）表达的降低。当用RANKL处理RAW264.7细胞时，雷公藤红素以剂量依赖的方式抑制TRAP + 多核细胞的形成和骨吸收活性。此外，雷公藤红素降低了RANKL诱导的破骨细胞基因和转录因子的表达，以及NF - kB和丝裂原活化蛋白激酶（MAPK）的磷酸化。这些发现表明，雷公藤红素可直接抑制破骨细胞的形成和功能，提示雷公藤红素在治疗类风湿关节炎，尤其是预防骨破坏方面有新的治疗策略。
