Understanding the expression of oligodendrocyte specific ADAMTS4 following a spinal cord injury and a potential modulator of its expression

Abstract

The average annual incidence of spinal cord injury (SCI) in New Zealand is 22 cases per million people. These patients have impairments to the anatomy and functioning of their cords that result in abolished transmission of sensory, motor, and autonomic information. This leads to chronic sensation loss, paralysis, and functional disabilities. This is in part due to the degeneration and loss of axons and the insulating myelin membrane that aids effective communication within the cord. Hyper-deposition of chondroitin sulfate proteoglycans (CSPGs) also occur post-injury and act as chronic inhibitors of regeneration. Previous work of ours and others have investigated the endogenous proteinase a disintegrin and metalloproteinase with thrombospondin motif 4 (ADAMTS4) and shown it can degrade CSPGs to promote functional recovery following SCI. Research has also determined endogenous ADAMTS4 is expressed by oligodendrocytes, the myelin-producing cell type of the spinal cord. This thesis investigates ADAMTS4 oligodendrocyte specific expression following a spinal cord injury and what factors are involved in influencing Adamts4 mRNA expression post-injury. Histological examination of spinal cord tissue from a rodent contusion SCI model revealed mature oligodendrocytes had a significant loss of ADAMTS4 at 1- and 7-days post-injury and a nonsignificant trend of recovery that spans the 2 weeks post-injury. Immature oligodendrocytes had a nonsignificant increase in ADAMTS4 from 1- to 28-days post-injury. Using primary rodent oligodendrocyte cultures and RT-qPCR, the effect of TGF-β, a vital cytokine in the development of the spinal cord injury, upon Adamts4 mRNA expression was studied. TGF-β did not influence the expression of Adamts4 in immature or maturing oligodendrocytes in vitro nor did it affect certain factors of a hypothesised regulatory pathway for Adamts4. TGF-β did downregulate certain oligodendrocyte specific genes in mature oligodendrocytes but this was independent of any Adamts4dependent effect. Collectively these findings suggest that ADAMTS4 in mature oligodendrocytes is downregulated after a spinal cord injury and that oligodendrocyte specific ADAMTS4 after an injury may differ between the differentiation stages of the cell. As well, these findings indicate that TGF-β alone does not affect Adamts4 mRNA expression in immature or newly differentiated mature oligodendrocytes.