title: Celastrol attenuates bone erosion in collagen-Induced arthritis mice and inhibits osteoclast differentiation and function in RANKL-induced RAW264.7.
abstract: 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.
authors.affiliation: 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.
authors.forename: Ke
authors.initials: K
authors.lastname: Gan
authors.affiliation: Department of Rheumatology, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, China.
authors.forename: Lingxiao
authors.initials: L
authors.lastname: Xu
authors.affiliation: Integrative Medicine Institute of Nanjing Medical University, 300 Guangzhou Road, Nanjing, China.
authors.forename: Xiaoke
authors.initials: X
authors.lastname: Feng
authors.affiliation: Integrative Medicine Institute of Nanjing Medical University, 300 Guangzhou Road, Nanjing, China.
authors.forename: Qiande
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Rheumatology, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, China.
authors.forename: Miaojia
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Rheumatology, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, China. Electronic address: tw2006@njmu.edu.cn.
authors.forename: Wenfeng
authors.initials: W
authors.lastname: Tan
mesh_terms: D000135:Acid Phosphatase / Q000378:metabolism; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D001862:Bone Resorption / Q000188:drug therapy*; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D007596:Joints / Q000187:drug effects* / Q000473:pathology; D008516:Medicine, Chinese Traditional; D051379:Mice; D008815:Mice, Inbred Strains; D010010:Osteoclasts / Q000187:drug effects*; D053978:Pentacyclic Triterpenes; D053245:RANK Ligand / Q000378:metabolism; D000071681:Tartrate-Resistant Acid Phosphatase; D015533:Transcriptional Activation / Q000187:drug effects; D029757:Tripterygium / Q000276:immunology; D014315:Triterpenes / Q000008:administration & dosage*
chemical_list: D007527:Isoenzymes; D053978:Pentacyclic Triterpenes; D053245:RANK Ligand; D014315:Triterpenes; D000135:Acid Phosphatase; C000605511:Acp5 protein, mouse; D000071681:Tartrate-Resistant Acid Phosphatase; C050414:celastrol
keywords: Celastrol; Collagen-Induced arthritis; Osteoclast