DDRGK1 preserves intervertebral disc development through ufmylation.

Area of Science:

• Biochemistry and Molecular Biology
• Developmental Biology
• Orthopedics

Background:

• UFMylation is a vital post-translational modification impacting cell development.
• The role of UFMylation, specifically DDRGK1, in intervertebral disc development is largely unknown.
• Intervertebral disc degeneration is a significant clinical challenge.

Purpose of the Study:

• To investigate the function of DDRGK1 in intervertebral disc development and degeneration.
• To elucidate the molecular mechanisms underlying DDRGK1's role in nucleus pulposus and cartilage endplate cells.

Main Methods:

• Generation of Ddrgk1 conditional knockout (cKO) mice (Ddrgk1^fl/fl; Acan-CreER^T2).
• Analysis of spinal growth, disc cellularity, and degeneration in Ddrgk1 cKO mice.
• RNA sequencing and immunohistochemical analysis of disc tissues.
• Assessment of disc degeneration following lumbar spine instability surgery.

Main Results:

• Ddrgk1 conditional knockout severely impaired spinal growth and initiated disc degeneration.
• Late postnatal knockout led to profound disc degeneration, particularly affecting cartilage endplate thickness.
• Ddrgk1 cKO mice showed exacerbated degeneration after instability surgery.
• Upregulation of apoptosis, ECM degradation, and ER stress pathways observed in Ddrgk1-deficient discs.

Conclusions:

• DDRGK1 is essential for maintaining intervertebral disc cellularity and structure.
• DDRGK1 regulates cell fate, ER homeostasis, and extracellular matrix metabolism in the disc.
• DDRGK1 deficiency leads to intervertebral disc degeneration through apoptosis, ECM breakdown, and ER stress.