Genotoxic stress accelerates age-associated degenerative changes in intervertebral discs

Area of Science:

• Biomedical Science
• Molecular Biology
• Genetics

Background:

• Intervertebral disc degeneration (IDD) is a primary cause of chronic lower back pain, with aging as the main risk factor.
• Previous research linked IDD to a progeroid syndrome model with reduced DNA repair enzyme expression.
• A hypothesis was formed that DNA damage actively promotes IDD progression.

Purpose of the Study:

• To investigate the causal relationship between DNA damage and intervertebral disc degeneration.
• To determine the impact of genotoxic stress on disc matrix composition, cellularity, and structural integrity.

Main Methods:

• Adult wild-type (Wt) and DNA repair-deficient Ercc1(-/Δ) mice were chronically exposed to mechlorethamine (MEC) or ionizing radiation (IR) to induce DNA damage.
• Disc structure, proteoglycan (PG) content, ADAMTS4 expression, aggrecan fragments, PG synthesis, cellular senescence, and apoptosis were measured.
• Local vertebral irradiation was performed in Wt mice as a comparative model.

Main Results:

• MEC and IR exposure significantly reduced proteoglycan content (3-5×) and new PG synthesis (2-3×) in mouse discs.
• Increased expression of ADAMTS4 and aggrecan fragments, alongside elevated cellular senescence and apoptosis, were observed in treated discs.
• DNA repair-deficient Ercc1(-/Δ) mice exhibited more severe degenerative changes compared to Wt mice, indicating a role for DNA repair capacity.

Conclusions:

• Genotoxic stress, induced by agents like MEC or IR, drives degenerative changes characteristic of intervertebral disc degeneration.
• DNA damage significantly impairs disc matrix homeostasis and promotes cellular damage pathways.
• The findings highlight the critical role of DNA integrity in maintaining spinal health and preventing disc degeneration.