title: Human neuropathological and animal model evidence supporting a role for Fas-mediated apoptosis and inflammation in cervical spondylotic myelopathy.
abstract: Although cervical spondylotic myelopathy is a common cause of chronic spinal cord dysfunction in humans, little is known about the molecular mechanisms underlying the progressive neural degeneration characterized by this condition. Based on animal models of cervical spondylotic myelopathy and traumatic spinal cord injury, we hypothesized that Fas-mediated apoptosis and inflammation may play an important role in the pathobiology of human cervical spondylotic myelopathy. We further hypothesized that neutralization of the Fas ligand using a function-blocking antibody would reduce cell death, attenuate inflammation, promote axonal repair and enhance functional neurological outcomes in animal models of cervical spondylotic myelopathy. We examined molecular changes in post-mortem human spinal cord tissue from eight patients with cervical spondylotic myelopathy and four control cases. Complementary studies were conducted using a mouse model of cervical spondylotic myelopathy (twy/twy mice that develop spontaneous cord compression at C2-C3). We observed Fas-mediated apoptosis of neurons and oligodendrocytes and an increase in inflammatory cells in the compressed spinal cords of patients with cervical spondylotic myelopathy. Furthermore, neutralization of Fas ligand with a function-blocking antibody in twy/twy mice reduced neural inflammation at the lesion mediated by macrophages and activated microglia, glial scar formation and caspase-9 activation. It was also associated with increased expression of Bcl-2 and promoted dramatic functional neurological recovery. Our data demonstrate, for the first time in humans, the potential contribution of Fas-mediated cell death and inflammation to the pathobiology of cervical spondylotic myelopathy. Complementary data in a murine model of cervical spondylotic myelopathy further suggest that targeting the Fas death receptor pathway is a viable neuroprotective strategy to attenuate neural degeneration and optimize neurological recovery in cervical spondylotic myelopathy. Our findings highlight the possibility of medical treatments for cervical spondylotic myelopathy that are complementary to surgical decompression.
authors.affiliation: Department of Pathology, Toronto Western Research Institute, Krembil Neuroscience Centre, Toronto Western Hospital, University Health Network, and University of Toronto, Room 4W-449, 399 Bathurst Street, Toronto, Ontario M5T 2S8, Canada.
authors.forename: Wen Ru
authors.initials: WR
authors.lastname: Yu
authors.forename: Tianyi
authors.initials: T
authors.lastname: Liu
authors.forename: Tim-Rasmus
authors.initials: TR
authors.lastname: Kiehl
authors.forename: Michael G
authors.initials: MG
authors.lastname: Fehlings
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D000818:Animals; D000906:Antibodies / Q000627:therapeutic use; D017209:Apoptosis / Q000502:physiology*; D001835:Body Weight; D053453:Caspase 9 / Q000378:metabolism; D002574:Cervical Vertebrae / Q000473:pathology*; D002921:Cicatrix / Q000209:etiology; D004195:Disease Models, Animal; D053222:Fas Ligand Protein / Q000276:immunology; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D020287:In Situ Nick-End Labeling / Q000379:methods; D007249:Inflammation / Q000188:drug therapy / Q000209:etiology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008817:Mice, Mutant Strains; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009836:Oligodendroglia; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011597:Psychomotor Performance; D013118:Spinal Cord Diseases / Q000150:complications* / Q000188:drug therapy; D013128:Spinal Osteophytosis / Q000150:complications* / Q000188:drug therapy; D013997:Time Factors; D019014:fas Receptor / Q000378:metabolism*
chemical_list: C555337:APC protein, human; D025601:Adenomatous Polyposis Coli Protein; D000906:Antibodies; D053222:Fas Ligand Protein; D005904:Glial Fibrillary Acidic Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D019014:fas Receptor; D053453:Caspase 9