Analysis of Nkx3.1:Cre-driven Erk5 deletion reveals a profound spinal deformity which is linked to increased osteoclast activity

Sci Rep. 2017 Oct 16;7(1):13241. doi: 10.1038/s41598-017-13346-8.

Abstract

Extracellular signal-regulated protein kinase 5 (ERK5) has been implicated during development and carcinogenesis. Nkx3.1-mediated Cre expression is a useful strategy to genetically manipulate the mouse prostate. While grossly normal at birth, we observed an unexpected phenotype of spinal protrusion in Nkx3.1:Cre;Erk5 fl/fl (Erk5 fl/fl) mice by ~6-8 weeks of age. X-ray, histological and micro CT (µCT) analyses showed that 100% of male and female Erk5 fl/fl mice had a severely deformed curved thoracic spine, with an associated loss of trabecular bone volume. Although sex-specific differences were observed, histomorphometry measurements revealed that both bone resorption and bone formation parameters were increased in male Erk5 fl/fl mice compared to wild type (WT) littermates. Osteopenia occurs where the rate of bone resorption exceeds that of bone formation, so we investigated the role of the osteoclast compartment. We found that treatment of RANKL-stimulated primary bone marrow-derived macrophage (BMDM) cultures with small molecule ERK5 pathway inhibitors increased osteoclast numbers. Furthermore, osteoclast numbers and expression of osteoclast marker genes were increased in parallel with reduced Erk5 expression in cultures generated from Erk5 fl/fl mice compared to WT mice. Collectively, these results reveal a novel role for Erk5 during bone maturation and homeostasis in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Resorption / genetics
  • Cancellous Bone / abnormalities
  • Cathepsin K / biosynthesis
  • Cell Count
  • Female
  • Gene Deletion
  • Homeodomain Proteins / metabolism
  • Integrases / genetics
  • Lymphocyte Activation
  • Male
  • Mice
  • Mice, Transgenic
  • Mitogen-Activated Protein Kinase 7 / genetics
  • Mitogen-Activated Protein Kinase 7 / physiology*
  • NFATC Transcription Factors / biosynthesis
  • Osteoclasts / metabolism*
  • Osteogenesis / genetics
  • Receptor Activator of Nuclear Factor-kappa B / biosynthesis
  • Spine / abnormalities*
  • Transcription Factors / metabolism

Substances

  • Homeodomain Proteins
  • NFATC Transcription Factors
  • Nfatc1 protein, mouse
  • Nkx3-1 protein, mouse
  • Receptor Activator of Nuclear Factor-kappa B
  • Tnfrsf11a protein, mouse
  • Transcription Factors
  • Mitogen-Activated Protein Kinase 7
  • Cre recombinase
  • Integrases
  • Cathepsin K
  • Ctsk protein, mouse