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

• Published in: Scientific reports Vol. 7; no. 1; pp. 13241 - 12
• Main Authors: Loveridge, Carolyn J., van ’t Hof, Rob J., Charlesworth, Gemma, King, Ayala, Tan, Ee Hong, Rose, Lorraine, Daroszewska, Anna, Prior, Amanda, Ahmad, Imran, Welsh, Michelle, Mui, Ernest J., Ford, Catriona, Salji, Mark, Sansom, Owen, Blyth, Karen, Leung, Hing Y.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16-10-2017; Nature Publishing Group
• Subjects: 13/106; 13/51; 14/34; 14/63; 38/77; 631/136/818; 631/80/86/820; 64/110; 64/60; Animals; Bone growth; Bone histomorphometry; Bone marrow; Bone resorption; Bone Resorption - genetics; Cancellous bone; Cancellous Bone - abnormalities; Carcinogenesis; Cathepsin K - biosynthesis; Cell Count; Female; Gene Deletion; Homeodomain Proteins - metabolism; Homeostasis; Humanities and Social Sciences; Integrases - genetics; Kinases; Lymphocyte Activation; Macrophages; Male; Mice; Mice, Transgenic; Mitogen-Activated Protein Kinase 7 - genetics; Mitogen-Activated Protein Kinase 7 - physiology; multidisciplinary; NFATC Transcription Factors - biosynthesis; Nkx3.1 protein; Osteoclasts - metabolism; Osteogenesis; Osteogenesis - genetics; Osteopenia; Prostate; Protein kinase; Receptor Activator of Nuclear Factor-kappa B - biosynthesis; Rodents; Science; Science (multidisciplinary); Spine; Spine (thoracic); Spine - abnormalities; TRANCE protein; Transcription Factors - metabolism
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-13346-8

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
.