Accelerated Senescence in Degenerate Intervertebral Disc of Laminopathy-based Premature Aging Mouse Model

Abstract

Lamin A/C, nuclear proteins from alternative spliced forms of LMNA gene, are type-V intermediate filament proteins. Various mutations have been identified in LMNA gene in a lot of human disorders including muscular dystrophy, cardiomyopathy and premature aging, which collectively called laminopathies. Lamin A comes from the processing of prelamin A by Zmpste24, a multispanning membrane protein widely distributed in mammalian tissues. Mice lacking Zmpste24 recapitulate many of the phenotypes observed in HGPS (Hutchinson-Gilford Progeria Syndrome) patients including short lifespan, decreased body weight and smaller body size. This is a good mouse model for aging research. As low back pain is usually developed in the aging people and IDD (intervertebral disc degeneration) is believed the most common reason for low back pain. We investigate in this study whether this premature aging mouse model develop IDD and can be an IDD model. Smaller nucleus pulposus, abnormal annulus fibrosus structure and decreased disc height were found in the endstage zmpste24 deficient mice disc. Which is consistent with the criteria of human intervertebral disc degeneration. MRI analysis show the disc signal of mutant mice is less than wild type mice due to the decreased nucleus pulposus size. While in contrast to the criteria of human intervertebral disc degeneration., the cells in the nucleus pulposus increase instead of decreasing demonstrated by DAPI staining. Senescence-associated β-gal (SA-β gal) staining show accelerated senescence in the zmpste24 deficient mice disc even at younger stage the same as reported in the human degenerated intervertebral disc. Our results show the zmpste24 deficient mice can be a good model for intervertebral disc degeneration research.