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

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.

SUBMITTER: Loveridge CJ

PROVIDER: S-EPMC5643304 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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

Loveridge Carolyn J CJ van 't Hof Rob J RJ Charlesworth Gemma G King Ayala A Tan Ee Hong EH Rose Lorraine L Daroszewska Anna A Prior Amanda A Ahmad Imran I Welsh Michelle M Mui Ernest J EJ Ford Catriona C Salji Mark M Sansom Owen O Blyth Karen K Leung Hing Y HY

Scientific reports 20171016 1

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 ha ...[more]

PMID: 29038439

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Project description:BackgroundAdult spinal deformity patients (ASD) experience altered spinal alignment affecting spatiotemporal parameters and joint kinematics. Differences in spinal deformity between patients with symptomatic idiopathic scoliosis (ID-ASD) and patients with "de novo" scoliosis (DN-ASD) may affect gait characteristics differently. This study aims to compare gait characteristics between ID-ASD, DN-ASD, and asymptomatic healthy matched controls.MethodsIn this observational case-control study, ID-ASD (n = 24) and DN-ASD (n = 26) patients visiting the out-patient spine clinic and scheduled for long-segment spinal fusion were included. Patients were matched, based on age, gender, leg length and BMI, with asymptomatic healthy controls. Gait was measured at comfortable walking speed on an instrumented treadmill with 3D motion capture system. Trunk, pelvic and lower extremities range of motion (ROM) and spatiotemporal parameters (SPT) are presented as median (first and thirds quartile). Independent t-test or Mann-Whitney U test was used to compare ID-ASD, DN-ASD and controls. Statistical Parametric Mapping (independent t-test) was used to compare 3D joint kinematics.ResultsDN-ASD patients walk with increased anterior trunk tilt during the whole gait cycle compared with ID-ASD patients and controls. ID-ASD walk with decreased trunk lateroflexion compared with DN-ASD and controls. DN-ASD showed decreased pelvic obliquity and -rotation, increased knee flexion, and decreased ankle plantar flexion. ID-ASD and DN-ASD displayed decreased trunk, pelvic and lower extremity ROM compared with controls, but increased pelvic tilt ROM. ID-ASD patients walked with comparable SPT to controls, whereas DN-ASD patients walked significantly slower with corresponding changes in SPT and wider steps.ConclusionsDN-ASD patients exhibit distinct alterations in SPT and kinematic gait characteristics compared with ID-ASD and controls. These alterations seem to be predominantly influenced by sagittal spinal malalignment and kinematic findings in ASD patients should not be generalized as such, but always be interpreted with consideration for the nature of the ASD.

Project description:Spinal alignment measurement in spinal deformity research has recently shifted from using mainly two-dimensional static radiography toward skin marker-based motion capture approaches, allowing three-dimensional (3D) assessments during dynamic conditions. The validity and accuracy of such skin marker-based methods is highly depending on correct marker placement. In this study we quantified, for the first time, the 3D spinal palpation error in adult spinal deformity (ASD) and compared it to the error in healthy spines. Secondly, the impact of incorrect marker placement on the accuracy of marker-based spinal alignment measurement was investigated. 3D, mediolateral and inferosuperior palpation errors for thoracolumbar and lumbar vertebral levels were measured on biplanar images by extracting 3D positions of skin-mounted markers and their corresponding anatomical landmarks in 20 ASD and 10 healthy control subjects. Relationships were investigated between palpation error and radiographic spinal alignment (lordosis and scoliosis), as well as body morphology [BMI and soft tissue (ST) thickness]. Marker-based spinal alignment was measured using a previously validated method, in which a polynomial is fit through the marker positions of a motion trial and which allows for radiograph-based marker position correction. To assess the impact of palpation error on spinal alignment measurement, the agreement was investigated between lordosis and scoliosis measured by a polynomial fit through, respectively, (1) the uncorrected marker positions, (2) the palpation error-corrected (optimal) marker positions, and (3) the anatomically corrected marker positions (toward the vertebral body), and their radiographic equivalents expressed as Cobb angles (ground truth), using Spearman correlations and root mean square errors (RMSE). The results of this study showed that, although overall accuracy of spinal level identification was similar across groups, mediolateral palpation was less accurate in the ASD group (ASDmean: 6.8 mm; Controlmean: 2.5 mm; p = 0.002). Significant correlations with palpation error indicated that determining factors for marker misplacement were spinal malalignment, in particular scoliotic deformity (r = 0.77; p < 0.001), in the ASD group and body morphology [i.e., increased BMI (r s = 0.78; p = 0.008) and ST thickness (r s = 0.66; p = 0.038)] in healthy spines. Improved spinal alignment measurements after palpation error correction, shows the need for radiograph-based marker correction methods, and therefore, should be considered when interpreting spinal kinematics.

Dataset Information

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

Publications

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

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