Harpagoside Inhibits RANKL-Induced Osteoclastogenesis via Syk-Btk-PLCγ2-Ca(2+) Signaling Pathway and Prevents Inflammation-Mediated Bone Loss

J Nat Prod. 2015 Sep 25;78(9):2167-74. doi: 10.1021/acs.jnatprod.5b00233. Epub 2015 Aug 26.

Abstract

Harpagoside (HAR) is a natural compound isolated from Harpagophytum procumbens (devil's claw) that is reported to have anti-inflammatory effects; however, these effects have not been investigated in the context of bone development. The current study describes for the first time that HAR inhibits receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclastogenesis in vitro and suppresses inflammation-induced bone loss in a mouse model. HAR also inhibited the formation of osteoclasts from mouse bone marrow macrophages (BMMs) in a dose-dependent manner as well as the activity of mature osteoclasts, including filamentous actin (F-actin) ring formation and bone matrix breakdown. This involved a HAR-induced decrease in extracellular signal-regulated kinase (ERK) and c-jun N-terminal kinase (JNK) phosphorylation, leading to the inhibition of Syk-Btk-PLCγ2-Ca(2+) in RANKL-dependent early signaling, as well as the activation of c-Fos and nuclear factor of activated T cells cytoplasmic 1 (NFATc1), which resulted in the down-regulation of various target genes. Consistent with these in vitro results, HAR blocked lipopolysaccharide (LPS)-induced bone loss in an inflammatory osteoporosis model. However, HAR did not prevent ovariectomy-mediated bone erosion in a postmenopausal osteoporosis model. These results suggest that HAR is a valuable agent against inflammation-related bone disorders but not osteoporosis induced by hormonal abnormalities.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Down-Regulation / drug effects
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Female
  • Glycosides / chemistry
  • Glycosides / pharmacology*
  • Inflammation / metabolism
  • Inflammation Mediators
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Macrophages / drug effects
  • Mice
  • Mitogen-Activated Protein Kinases / metabolism
  • Molecular Structure
  • Osteoclasts / drug effects*
  • Phospholipase C gamma
  • Proto-Oncogene Proteins c-fos / genetics
  • Pyrans / chemistry
  • Pyrans / pharmacology*
  • RANK Ligand / pharmacology
  • Receptor Activator of Nuclear Factor-kappa B
  • Signal Transduction / drug effects*

Substances

  • Glycosides
  • Inflammation Mediators
  • Proto-Oncogene Proteins c-fos
  • Pyrans
  • RANK Ligand
  • Receptor Activator of Nuclear Factor-kappa B
  • harpagoside
  • Extracellular Signal-Regulated MAP Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • Phospholipase C gamma