Kinin B1 and B2 receptor expression in osteoblasts and fibroblasts is enhanced by interleukin-1 and tumour necrosis factor-alpha. Effects dependent on activation of NF-kappaB and MAP kinases

Bone. 2008 Jul;43(1):72-83. doi: 10.1016/j.bone.2008.02.003. Epub 2008 Mar 10.


Pro-inflammatory mediators formed by the kallikrein-kinin system can stimulate bone resorption and synergistically potentiate bone resorption induced by IL-1 and TNF-alpha. We have shown that the effect is associated with synergistically enhanced RANKL expression and enhanced prostaglandin biosynthesis, due to increased cyclooxygenase-2 expression. In the present study, the effects of osteotropic cytokines and different kinins on the expression of receptor subtypes for bradykinin (BK), des-Arg10-Lys-BK (DALBK), IL-1beta and TNF-alpha have been investigated. IL-1beta and TNF-alpha enhanced kinin B1 and B2 receptor binding in the human osteoblastic cell line MG-63 and the mRNA expression of B1 and B2 receptors in MG-63 cells, human gingival fibroblasts and intact mouse calvarial bones. Kinins did not affect mRNA expression of IL-1 or TNF receptors. EMSA showed that IL-1beta and TNF-alpha activated NF-kappaB and AP-1 in MG-63 cells. IL-1beta stimulated NF-kappaB via a non-canonical pathway (p52/p65) and TNF-alpha via the canonical pathway (p50/p65). Activation of AP-1 involved c-Jun in both IL-1beta and TNF-alpha stimulated cells, but c-Fos only in TNF-alpha stimulated cells. Phospho-ELISA and Western blots showed that IL-1beta activated JNK and p38, but not ERK 1/2 MAP kinase. Pharmacological inhibitors showed that NF-kappaB, p38 and JNK were important for IL-1beta induced stimulation of B1 receptors, and NF-kappaB and p38 for B2 receptors. p38 and JNK were important for TNF-alpha induced stimulation of B1 receptors, whereas NF-kappaB, p38 and JNK were involved in TNF-alpha induced expression of B2 receptors. These data show that IL-1beta and TNF-alpha upregulate B1 and B2 receptor expression by mechanisms involving activation of both NF-kappaB and MAP kinase pathways, but that signal transduction pathways are different for IL-1beta and TNF-alpha. The enhanced kinin receptor expression induced by the pro-inflammatory cytokines IL-1beta and TNF-alpha might be one important mechanism involved in the synergistic enhancement of prostaglandin formation caused by co-treatment with kinins and one of the two cytokines. These mechanisms might help to explain the enhanced bone resorption associated with inflammatory disorders, including periodontitis and rheumatoid arthritis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Cell Line, Tumor
  • DNA Primers
  • Electrophoretic Mobility Shift Assay
  • Enzyme Activation
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Humans
  • Interleukin-1 / pharmacology
  • Interleukin-1 / physiology*
  • Mitogen-Activated Protein Kinases / metabolism*
  • NF-kappa B / metabolism*
  • Osteoblasts / drug effects
  • Osteoblasts / metabolism*
  • Phosphorylation
  • Radioligand Assay
  • Receptor, Bradykinin B1 / drug effects
  • Receptor, Bradykinin B1 / genetics
  • Receptor, Bradykinin B1 / metabolism*
  • Receptor, Bradykinin B2 / drug effects
  • Receptor, Bradykinin B2 / genetics
  • Receptor, Bradykinin B2 / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Tumor Necrosis Factor-alpha / pharmacology
  • Tumor Necrosis Factor-alpha / physiology*


  • DNA Primers
  • Interleukin-1
  • NF-kappa B
  • Receptor, Bradykinin B1
  • Receptor, Bradykinin B2
  • Tumor Necrosis Factor-alpha
  • Mitogen-Activated Protein Kinases