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

Loveridge, C. J. et al. (2017) Analysis of Nkx3.1:Cre-driven Erk5 deletion reveals a profound spinal deformity which is linked to increased osteoclast activity. Scientific Reports, 7, 13241. (doi:10.1038/s41598-017-13346-8) (PMID:29038439) (PMCID:PMC5643304)

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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;Erk5fl/fl (Erk5fl/fl) mice by ~6–8 weeks of age. X-ray, histological and micro CT (µCT) analyses showed that 100% of male and female Erk5fl/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 Erk5fl/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 Erk5fl/fl mice compared to WT mice. Collectively, these results reveal a novel role for Erk5 during bone maturation and homeostasis in vivo.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Ahmad, Dr Imran and Tan, Dr Ee and Leung, Professor Hing and Blyth, Dr Karen and Loveridge, Ms Carolyn and Ford, Miss Catriona and Mui, Mr Ernest and Salji, Dr Mark and King, Dr Ayala and Sansom, Professor Owen and Welsh, Dr Michelle
Authors: Loveridge, C. J., van ’t Hof, R. J., Charlesworth, G., King, A., Tan, E. H., Rose, L., Daroszewska, A., Prior, A., Ahmad, I., Welsh, M., Mui, E. J., Ford, C., Salji, M., Sansom, O., Blyth, K., and Leung, H. Y.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Scientific Reports
Publisher:Nature Publishing Group
ISSN:2045-2322
ISSN (Online):2045-2322
Copyright Holders:Copyright © 2017 The Authors
First Published:First published in Scientific Reports 7:13241
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
565981Synergistic interaction between Sprouty2 loss and PI3K/AKT activation in prostate carcinogenesisHing LeungProstate Cancer UK (PROSCANU)PG10-10RI CANCER SCIENCES