Genotoxic stress accelerates age-associated degenerative changes in intervertebral discs

Abstract

Intervertebral disc degeneration (IDD) is the leading cause of debilitating spinal disorders such as chronic lower back pain. Aging is the greatest risk factor for IDD. Previously, we demonstrated IDD in a murine model of a progeroid syndrome caused by reduced expression of a key DNA repair enzyme. This led us to hypothesize that DNA damage promotes IDD. To test our hypothesis, we chronically exposed adult wild-type (Wt) and DNA repair-deficient Ercc1−/Δ mice to the cancer therapeutic agent mechlorethamine (MEC) or ionization radiation (IR) to induce DNA damage and measured the impact on disc structure. Proteoglycan, a major structural matrix constituent of the disc, was reduced 3-5x in the discs of MEC- and IR-exposed animals compared to untreated controls. Expression of the protease ADAMTS4 and aggrecan proteolytic fragments were significantly increased. Additionally, new PG synthesis was reduced 2-3x in MEC- and IR-treated discs compared to untreated controls. Both cellular senescence and apoptosis were increased in discs of treated animals. The effects were more severe in the DNA repair-deficient Ercc1−/Δ mice than in Wt littermates. Local irradiation of the vertebra in Wt mice elicited a similar reduction in PG. These data demonstrate that genotoxic stress drives degenerative changes associated with IDD.

Single Nucleotide Variants of Candidate Genes in Aggrecan Metabolic Pathway Are Associated with Lumbar Disc Degeneration and Modic Changes

“…According to animal studies increased expression of the ADAMTS4 gene accelerates the extracellular matrix breakdown and reduces synthesis of proteoglycan in the intervertebral disc [55, 56]. Each additional “C” allele of the rs41270041 variant of the ADAMTS4 gene reduced the severity of LDD in our sample, but this SNV did not have a significant association with LDD in the Chinese Han Population [23].…”

Pathomechanism of intervertebral disc degeneration

“…For example, Ercc1 −/Δ mice, in which ERCC1‐XPF is deficient (involved in DNA damage repair), showed typical features of disc aging, including loss of proteoglycan, decreased IVD height, and an increase in the number of senescent cells . The evidence that genotoxic stresses such as tobacco smoking or radiation cause disc aging further supports that DNA damage contributes to disc aging . Other possible causes of DNA damage include oxidative stress induced by inflammation.…”

Molecular mechanisms of biological aging in intervertebral discs

“…Indeed, DNA repair‐deficient Ercc1 −/Δ mice exhibit premature onset of key disc aging features, including loss of matrix proteoglycan, reduced disc height, and increased cellular senescence (Table ). DNA damage as a driver of disc aging is further supported by exposure studies of human and mice to genotoxic stress, including ionizing radiation and tobacco smoking, which in mice dramatically accelerated disc degenerative changes …”

“…DNA damage as a driver of disc aging is further supported by exposure studies of human and mice to genotoxic stress, including ionizing radiation and tobacco smoking, which in mice dramatically accelerated disc degenerative changes. [66][67][68] Stressors Driving Disc Biomolecular Damage Exogenous and endogenous stressors causing molecular damage in aging discs are thought to be predominantly oxidative and inflammatory in nature ( Fig. 3A).…”