Notch signaling inhibition protects against LPS mediated osteolysis

Biochem Biophys Res Commun. 2019 Aug 6;515(4):538-543. doi: 10.1016/j.bbrc.2019.05.166. Epub 2019 Jun 5.


Chronic inflammatory responses have profound effects on the differentiation and activity of both the bone-forming osteoblasts and bone-resorbing osteoclasts. Importantly, inflammatory bone diseases characterized by clinical osteolysis promote bone resorption and decrease bone formation by uncoupling the process in favor of excess resorption. Notch signaling regulates osteoclast development and thus its manipulation has the potential to suppress resorptive potential. Here, we have utilized a genetic model of Notch inhibition in osteoclasts by expression of dnMAML to prevent formation of transcriptional complex essential for downstream Notch signaling. Using this model and LPS as a tool for experimental inflammatory osteolysis, we have demonstrated that dnMAML-expressing osteoclasts exhibited significantly lower maturation and resorption/functional potential ex vivo using TRAP staining and calcium phosphate coated surfaces. Moreover, we observed that while LPS stimulated the formation of wildtype osteoclasts pre-treated with RANKL, dnMAML expression produced resistance to osteoclast maturation after LPS stimulation. Genetically, Notch-inhibited animals showed a significantly lower TRAP and CTX-1 levels in serum after LPS treatment compared to the control groups in addition to a marked reduction in osteoclast surfaces in calvaria sections. This report provides evidence for modulation of Notch signaling activity to protect against inflammatory osteolysis. Taken together, the findings of this study will help guide the development of Notch signaling-based therapeutic approaches to prevent bone loss.

Keywords: Calvaria; LPS; Notch signaling; Osteoclasts; TRAP; dnMAML.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Collagen Type I / blood
  • Collagen Type I / deficiency
  • Female
  • Lipopolysaccharides / pharmacology*
  • Mice
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Osteoclasts / cytology*
  • Osteoclasts / drug effects
  • Osteoclasts / metabolism
  • Osteolysis / prevention & control*
  • Peptides / blood
  • Peptides / deficiency
  • RANK Ligand / pharmacology
  • Receptors, Notch / biosynthesis
  • Receptors, Notch / deficiency*
  • Receptors, Notch / genetics
  • Receptors, Notch / metabolism
  • Signal Transduction* / drug effects
  • Signal Transduction* / genetics
  • Tartrate-Resistant Acid Phosphatase / blood
  • Tartrate-Resistant Acid Phosphatase / deficiency
  • Tartrate-Resistant Acid Phosphatase / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcription, Genetic


  • Collagen Type I
  • Lipopolysaccharides
  • Maml1 protein, mouse
  • Nuclear Proteins
  • Peptides
  • RANK Ligand
  • Receptors, Notch
  • Transcription Factors
  • collagen type I trimeric cross-linked peptide
  • Acp5 protein, mouse
  • Tartrate-Resistant Acid Phosphatase