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Published on: March 15, 2018

CXCL5 stimulation of RANK ligand expression in Paget's disease of bone

Kumaran Sundaram1, D Sudhaker Rao, William L Ries

  • 1Charles P Darby Children's Research Institute, Charleston, SC 29425, USA.

Laboratory Investigation; a Journal of Technical Methods and Pathology
|February 27, 2013
PubMed

Insights

Elevated CXCL5 levels, potentially linked to measles virus nucleocapsid protein (MVNP), drive increased RANKL expression in Paget's disease of bone (PDB). This suggests CXCL5 signaling, mediated by CREB, is a key factor in PDB pathogenesis.

Area of Science:

  • Bone Biology
  • Immunology
  • Virology

Background:

  • Paget's disease of bone (PDB) is a common skeletal disorder over age 55, characterized by heightened bone turnover and osteoclast hyperactivity.
  • The measles virus nucleocapsid protein (MVNP) is implicated in PDB pathogenesis.
  • CXCL5 mRNA and protein levels are significantly elevated in PDB patients.

Purpose of the Study:

  • To investigate the role of CXCL5 in Paget's disease of bone (PDB) pathogenesis.
  • To elucidate the molecular mechanisms by which CXCL5 influences bone turnover in PDB.

Main Methods:

  • Quantitative real-time PCR to measure mRNA expression (CXCL5, RANKL, CXCR1).
  • Western blotting to assess protein phosphorylation (ERK1/2, p38, CREB).
  • Chromatin immunoprecipitation (ChIP) assay to confirm transcription factor binding.

Main Results:

  • CXCL5 mRNA and serum levels were substantially increased in PDB patients.
  • MVNP transduction elevated CXCL5 expression in human bone marrow monocytes.
  • CXCL5 stimulation upregulated RANKL and CXCR1 expression, activating ERK1/2, p38, and CREB signaling pathways.
  • Phospho-CREB was confirmed to bind the RANKL gene promoter, mediating CXCL5-induced RANKL expression.

Conclusions:

  • CXCL5 is significantly elevated in PDB and contributes to increased RANKL expression.
  • CXCL5 signaling, through CREB activation, plays a crucial role in the enhanced bone turnover observed in PDB.
  • These findings highlight CXCL5 as a potential therapeutic target for Paget's disease of bone.

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