BME PhD Defense: Owen Papuga

The Development of a Murine Model of Compression Induced Vertebral Degeneration and the Development of Bone Marrow Edema

Abstract

The absence of predictable radiographic changes that correlate with painful vs. non-painful structural changes pose the greatest obstacle to progress in the effective evidence based treatment of chronic low back pain (LBP). Currently clinicians utilize Magnetic Resonance Imaging (MRI) as the most sensitive indicator of degeneration, using criteria developed by Michael Modic in which Modic Type 1 (MT1) MRI changes are associated with the early stages of chronic low back pain and used to designate those individuals who most likely benefit from surgical intervention. However, the nature of these Modic changes remains unknown. Thus, to the end of elucidating the cellular and biomechanical changes that lead to MT1 we propose the development of a mouse model utilizing chronically loaded tail vertebrae that closely resembles the radiology and histopathology of vertebral degeneration seen in humans.

Longitudinal studies of wild type mice and transgenic mice genetically modified to overproduce tumor necrosis factor (TNF-Tg) demonstrated significant differences in normalized marrow contrast enhancement (NMCE) values. From 8 to 12 weeks of age in wild type mice showed a significant decrease in NMCE values, while TNF-Tg mice maintained elevated values through 24 weeks of age. These elevated NMCE values corresponded to increased cellularity and vascularity found in the histomorphometric analysis of orange G and alcian blue (OG/AB) stained slides.

Longitudinal studies of loaded vertebrae demonstrated elevated NMCE values corresponding with an increase in cellularity and vascularity seen in histological analysis similar to that seen in the TNF-Tg mice. A transgenic knock out line of mice lacking the tumor necrosis factor receptor type1 and type 2 (TNFR1R2 -/-) failed to produce an increase in NMCE values when the same loading was applied. Those wild type mice placed under compressive loading and developing bone marrow edema failed to responded to Anti-TNF therapy and NMCE values were not significantly different from the placebo treated mice. These early experiments shed some light on the importance of TNF as a mediator of load induced degeneration of the spine.