Celastrol attenuates bone erosion in collagen-Induced arthritis mice and inhibits osteoclast differentiation and function in RANKL-induced RAW264.7

Int Immunopharmacol. 2015 Feb;24(2):239-246. doi: 10.1016/j.intimp.2014.12.012. Epub 2014 Dec 19.

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.

Keywords: Celastrol; Collagen-Induced arthritis; Osteoclast.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acid Phosphatase / metabolism
  • Animals
  • Arthritis, Experimental / drug therapy*
  • Arthritis, Rheumatoid / drug therapy*
  • Bone Resorption / drug therapy*
  • Cell Differentiation / drug effects
  • Cell Differentiation / genetics
  • Cell Line
  • Gene Expression Regulation / drug effects
  • Humans
  • Isoenzymes / metabolism
  • Joints / drug effects*
  • Joints / pathology
  • Medicine, Chinese Traditional*
  • Mice
  • Mice, Inbred Strains
  • Osteoclasts / drug effects*
  • Pentacyclic Triterpenes
  • RANK Ligand / metabolism
  • Tartrate-Resistant Acid Phosphatase
  • Transcriptional Activation / drug effects
  • Tripterygium / immunology
  • Triterpenes / administration & dosage*

Substances

  • Isoenzymes
  • Pentacyclic Triterpenes
  • RANK Ligand
  • Triterpenes
  • Acid Phosphatase
  • Acp5 protein, mouse
  • Tartrate-Resistant Acid Phosphatase
  • celastrol