Impaired Annulus Fibrosus Development and Vertebral Fusion Cause Severe Scoliosis in Mice with Deficiency of c-Jun NH2-Terminal Kinases 1 and 2

Authors

Veronica Ulici, The University of North Carolina at Chapel Hill
Kathryn L. Kelley, The University of North Carolina at Chapel Hill
Lara Longobardi, The University of North Carolina at Chapel Hill
Margaret A. McNulty, Indiana University School of Medicine
Eric W. Livingston, The University of North Carolina at Chapel Hill
Ted A. Bateman, The University of North Carolina at Chapel Hill
Cheryle A. Séguin, Western University
Craig R. Louer, The University of North Carolina at Chapel Hill
Richard F. Loeser, The University of North Carolina at Chapel Hill

Document Type

Article

Publication Date

4-1-2019

Journal

American Journal of Pathology

Volume

189

Issue

4

First Page

868

Last Page

885

URL with Digital Object Identifier

10.1016/j.ajpath.2018.12.010

Abstract

© 2019 American Society for Investigative Pathology Mitogen-activated protein kinases, including c-Jun NH2-terminal kinase (JNK), play an important role in the development and function of a large variety of tissues. The skeletal phenotype of JNK1 and JNK2 double-knockout (dKO) mice (JNK1 fl/fl Col2-Cre/JNK2 −/− ) and control genotypes were analyzed at different embryonic and postnatal stages. JNK1/2 dKO mice displayed a severe scoliotic phenotype beginning during development that was grossly apparent around weaning age. Alcian blue staining at embryonic day 17.5 showed abnormal fusion of the posterior spinal elements. In adult mice, fusion of vertebral bodies and of spinous and transverse processes was noted by micro–computed tomography, Alcian blue/Alizarin red staining, and histology. The long bones developed normally, and histologic sections of growth plate and articular cartilage revealed no significant abnormalities. Histologic sections of the vertebral column at embryonic days 15.5 and 17.5 revealed an abnormal organization of the annulus fibrosus in the dKOs, with chondrocyte-like cells and fusion of dorsal processes. Spinal sections in 10-week–old dKO mice showed replacement of intervertebral disk structures (annulus fibrosus and nucleus pulposus) by cartilage and bone tissues, with cells staining for markers of hypertrophic chondrocytes, including collagen X and runt-related transcription factor 2. These findings demonstrate a requirement for both JNK1 and JNK2 in the normal development of the axial skeleton. Loss of JNK signaling results in abnormal endochondral bone formation and subsequent severe scoliosis.

Notes

Article is freely available from the journal