Master of Kinesiology (MKin)
Faculty of Science
Study Design. In vivo examination of the influence of TAK-242 (resatorvid) treatment on the mechanical properties of the intervertebral disc (IVD) in secreted protein acidic and rich in cysteine (SPARC) gene knockout (SPARC-null) mice.
Objectives. To examine if chronic TAK-242 treatment mitigates mechanical degradation associated with IVD degeneration in SPARC-null mice.
Summary of Background data. IVD degeneration is associated with low back pain (LBP) and is accompanied by mechanical changes to the spine. SPARC is a protein that contributes to the functioning and maintenance of the extracellular matrix (ECM), with SPARC-null mice displaying accelerated IVD degeneration. TAK-242 is a toll-like receptor 4 (TLR4) inhibitor shown to decrease proinflammatory cytokines and pain.
Methods. SPARC-null (n=29) and WT (n=26) mice aged 7-9 months were injected with TAK-242 or an equivalent volume of saline for 8 weeks (3x/per week, M-W-F). Ten spines from each group were dissected and subjected to mechanical testing. Excised lumbar spines were tested in cyclic axial tension and compression to determine neutral zone (NZ) length, NZ stiffness, compressive stiffness, tensile stiffness, and hysteresis energy.
Results. TAK-242 treatment did not impact measures of NZ stiffness (p=0.30 ) and length (p=0.072) despite increasing hysteresis energy (p=0.036), and normalized hysteresis energy (p=0.047). SPARC-null mice presented with smaller (p=0.008) and stiffer (p=0.001) NZs than WT mice, regardless of treatment type. Tensile stiffness was greater in SPARC-null animals (p=0.025) but both tensile and compressive stiffness were not impacted by TAK-242 (p=0.045 and p=0.349 respectively). There was a near significant effect of mouse type on compressive stiffness; showing increased compressive stiffness in SPARC-null mice. NZ and compressive stiffness were reduced as a result of TAK-242 treatment in WT mice but not SPARC-null mice ((p=0.169 and p=0.148 respectively); suggesting a blunted effect of TAK-242 treatment in the SPARC-null model.
Conclusion. SPARC-null spines had smaller and stiffer NZs than WT mice, but TAK-242 treatment was not able to attenuate NZ changes associated with IVD degeneration in SPARC-null mice. Despite this, TAK-242 did increase hysteresis energy - indicating that hysteresis might be a more sensitive measure to detect changes to the IVD state. Reduced NZ and compressive stiffness in WT mice as a result of TAK-242 treatment indicates a blunted effect of TAK-242 in SPARC-null mice.
Whittal, Mitch, "TOLL-LIKE RECEPTOR 4 INHIBITION DIFFERENTIALLY IMPACTS INTERVERTEBRAL DISC AXIAL MECHANICS IN WILD TYPE AND SPARC-NULL MICE" (2020). Theses and Dissertations (Comprehensive). 2296.
Available for download on Saturday, August 19, 2023