Molecular mechanisms of spinal cord dysfunction and cell death in the spinal hyperostotic mouse: implications for the pathophysiology of human cervical spondylotic myelopathy.
Cervical spondylotic myelopathy (CSM) is the most common cause of spinal cord dysfunction in adults in Western society. Paradoxically, relatively little is known about the pathobiological mechanisms associated with the progressive loss of neural tissue in the spinal cord of CSM patients. In this report we have utilized the twy/twy mutant mouse, which develops ossification of the ligamentum flavum at C2-C3 and exhibits progressive paralysis. This animal model represents an excellent in vivo model of CSM. This study reports novel evidence, which demonstrates that chronic extrinsic cervical spinal cord compression leads to Fas-mediated apoptosis of neurons and oligodendrocytes which is associated with activation of caspase-8, -9 and -3 and progressive neurological deficits. While surgical decompression will remain the mainstay of management of CSM, molecular therapies, which target Fas-mediated apoptosis could show promise as a complementary approach to maximize neurological recovery in this common spinal cord condition.
Yu
Wen-Ru
WR
Division of Genetics and Development, Toronto Western Research Institute and Krembil Neuroscience Centre, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada.
Baptiste
Darryl C
DC
Liu
Tianyi
T
Odrobina
Ewa
E
Stanisz
Greg J
GJ
Fehlings
Michael G
MG
D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D004195:Disease Models, Animal; D053222:Fas Ligand Protein / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein; D015576:Hyperostosis; D051379:Mice; D008817:Mice, Mutant Strains; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D009836:Oligodendroglia / Q000378:metabolism / Q000473:pathology; D009999:Ossification, Heterotopic; D010291:Paresis; D013117:Spinal Cord Compression / Q000473:pathology / Q000503:physiopathology*; D013118:Spinal Cord Diseases / Q000473:pathology / Q000503:physiopathology*; D055009:Spondylosis / Q000473:pathology / Q000503:physiopathology*; D019014:fas Receptor / Q000378:metabolism*
D053222:Fas Ligand Protein; C491899:Fas protein, mouse; C505658:Fasl protein, mouse; D005904:Glial Fibrillary Acidic Protein; D009419:Nerve Tissue Proteins; D019014:fas Receptor; C528900:glial fibrillary astrocytic protein, mouse; C505409:Casp3 protein, mouse; C505526:Casp8 protein, mouse; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9