Aging of mouse intervertebral disc and association with back pain

Abstract

With the increased burden of low back pain (LBP) in our globally aging population there is a need to develop preclinical models of LBP that capture clinically relevant features of physiological aging, degeneration, and disability. Here we assess the validity of using a mouse model system for age-related LBP by characterizing aging mice for features of intervertebral disc (IVD) degeneration, molecular markers of peripheral sensitization, and behavioral signs of pain. Compared to three-month-old and one-year-old mice, two-year-old mice show features typical of IVD degeneration including loss of disc height, bulging, innervation and vascularization in the caudal lumbar IVDs. Aging is also associated with the loss of whole-body bone mineral density in both male and female mice, but not associated with percent lean mass or body fat. Additionally, two-year-old mice have an accumulation of TRPA1 channels and sodium channels Na v 1.8 and Na v 1.9 in the L4 and L5 lumbar dorsal root ganglia consistent with changes in nociceptive signaling. Lastly, the effect of age, sex, and weight on mobility, axial stretching and radiating pain measures was assessed in male and female mice ranging from two months to two years in a general linear model. The model revealed that regardless of sex or weight, increased age was a predictor of greater reluctance to perform axial stretching and sensitivity to cold, but not heat in mice.

Development of an in vitro intervertebral disc innervation model to screen neuroinhibitory biomaterials

“…Additionally, recent evidence of innervation in discogenic neck pain supports a similar mechanism for discogenic LBP . Induced and age‐related disc degeneration in mouse and rat models have also exhibited increased disc innervation, including into the NP . These data demonstrate a strong link between disc degeneration, increased disc innervation, and discogenic pain.…”

Arp2/3 inactivation causes intervertebral disc and cartilage degeneration with dysregulated TonEBP-mediated osmoadaptation

“…The intrinsic intra-and interanimal variation in disc degeneration phenotypes of lumbar and caudal discs at 6 month and 1 year was noted and is shown in Supplemental Figure 2. Indeed, genetic interactions with environmental stimuli have been indicated to substantially differ between lumbar levels in twin studies, and the biomechanical environment has been shown to differ significantly level by level along the spinal column, resulting in level-specific phenotypic outcomes (30,(39)(40)(41)(42). Although it is plausible that the phenotypic variability between animals was caused by some variation in recombination efficiencies of the floxed allele, the overall recombination is high, regardless of the spinal level.…”

“…Significance between collagen fiber distributions was determined by χ 2 test. Since the unique interactions between genetic, biological, and biomechanical factors at individual spinal levels have been shown to produce different phenotypic outcomes, each disc was considered as an independent sample (30,(40)(41)(42). All statistical analyses were done using Prism 7 (GraphPad Software).…”

Diet-induced Obesity Leads to Behavioral Indicators of Pain Preceding Structural Joint Damage in Wild-Type Mice.

“…In fact, recent studies demonstrated that mice fed a high-fat diet for 8 weeks showed increased time immobile in tail suspension, interpreted as a characteristic of depression-like behavior (56). This behavior is in contrast to both genetic and age-related mouse models of IVD degeneration and axial pain which show increased time rearing in tail suspension (57,58). This confounding factor may impact the outcome of tail suspension in the diet-induced obesity model, and consequently the interpretation of our ndings.…”