Intervertebral disc maintenance and repair potential in mice

Abstract

Intervertebral disc (IVD) degeneration is closely associated with low back pain, leading to disability, and presents an enormous clinical, psychological, and economic burden. While most people will develop disc degeneration with aging, some are more resistant, indicating the existence of protective genetic factors. The “healer” mice (LG/J and MRL/MpJ) have better regeneration of cartilaginous tissues compared to “poor healer” mice (C57BL/6J and SM/J). However, little is known about the changes and potential repair of the IVDs amongst these strains of mice. Here, I show differences in IVD maintenance with aging that correlates with different IVD self-repair capacities in mice, with SM/J mice developing degenerative changes as early as 8 weeks of age, while the IVDs in LG/J and MRL/MpJ mice maintained good disc structure for up to 1 year of age. The degenerative and protective mechanisms are likely to be complex, involving a combination of cellular and environmental events. The extracellular matrix (ECM) may play a major role, with higher levels of type I and type II collagens detected in the outer and inner annulus fibrosus (AF) of “healer” mice, respectively. This implicates the need to maintain tensile strength for better IVD homeostasis. In the nucleus pulposus (NP), there were differences in the levels of Tie2/GD2 expressing cells amongst LG/J, MRL/MpJ, and C57BL/6J mice, indicating an influence of genetic variation in cellular differentiation and progenitor cell levels. A tail-looping model was adopted to assess the IVD maintenance and self-repair potentials under mechanical stresses. With looping, the IVDs became wedge with major changes in the compressed AF. The inner and outer AF were separated with reversal of the inner compartment protruding into the NP region, and the outer part was compressed and squeezed towards the concave side, with death of AF cells. The NP and EP were also distorted from the uneven loading. With unlooping, repair from the induced degeneration occurred, which was better for the “healer” mice that included more efficient recovery of AF lamella reorganization and higher cellular content, NP expansion and repositioning within the center of the IVD, and re-establishment or better maintenance of the NP-AF boundary. The repair was concomitant with AF cell repopulation and ECM remodeling, with possible involvement of the inflammatory response, and the activation of the Wnt and TGFβ pathways. Surprisingly, a better long term IVD repair was evident in C57BL/6J mice with prolonged looping period comparing with the “healer” mice, which may attribute to the differences in the rate of ECM turnover and tissue regeneration. My study has highlighted the impact of genetic variations on IVD maintenance, and the self-repair capacity in mouse IVDs. This has opened up a new area of investigations using genetics and genomic to dissect the risk and protective genetic loci, and also the impact on cellular and IVD tissue functions that may be relevant to human disc biology and degeneration.