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.
Highlights
Extracellular signal-regulated protein kinase 5 (ERK5) (MAPK7 or BMK) belongs to the family of mitogen-activated protein kinases (MAPKs), members of which typically function as signalling nodes to integrate information from extracellular stimuli and different intracellular signalling cascades
While there was no difference in mineral apposition rate, we observed a significant increase in mineralizing surface per bone surface (MS/BS) and bone formation rate per bone surface (BFR/BS) in Erk5fl/fl males compared to wild type (WT)
We found that the low bone mass in male Erk5fl/fl mice was associated with increased bone-remodeling, with both significantly enhanced bone resorption and bone formation parameters being observed
Summary
ERK5 (MAPK7 or BMK) belongs to the family of mitogen-activated protein kinases (MAPKs), members of which typically function as signalling nodes to integrate information from extracellular stimuli and different intracellular signalling cascades Through this activity, MAPKs control numerous biological processes during development and homeostasis, including cellular proliferation, differentiation and survival. Erk[5] null mice die around embryonic day 10.5 due to cardiovascular defects with impaired vasculogenesis and angiogenesis This is consistent with findings that ERK5 plays a critical role in endothelial cell function[8,9]. We report increased osteoclast differentiation in primary bone marrow cultures generated from wild type (WT) mice treated with small molecule ERK5 pathway inhibitors and in mice with Nkx3.1:Cre-mediated Erk[5] deletion compared to WT, indicating a link between Erk[5] and osteoclast activity in vivo
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
