METTL3-mediated m⁶A modification promotes intervertebral disc degeneration

Area of Science:

• Epigenetics
• RNA modification
• Biochemistry

Background:

• N6-methyladenosine (m6A) modification is a crucial epigenetic regulator.
• METTL3 is the primary enzyme responsible for m6A catalysis.
• The role of m6A in intervertebral disc degeneration (IDD) requires further investigation.

Purpose of the Study:

• To investigate the function and mechanisms of METTL3-mediated m6A modification in IDD.
• To explore the potential of targeting METTL3 for IDD treatment.

Main Methods:

• Analysis of RNA sequencing data (GSE167199, GSE165722).
• Validation of m6A levels and gene expression in nucleus pulposus (NP) cells and tissues.
• In vitro gain- and loss-of-function experiments in NP cells.
• In vivo assessment of METTL3 inhibition and miR-338-3p suppression in IDD models.

Main Results:

• METTL3 overexpression accelerated NP cell apoptosis and senescence while inhibiting matrix synthesis.
• METTL3-mediated m6A modification enhanced pri-miR-338-3p production and maturation via DGCR8.
• METTL3 inhibition mitigated IDD progression in vivo.
• miR-338-3p suppression alleviated IDD during METTL3 overexpression.

Conclusions:

• Targeting METTL3 attenuates IDD progression via the METTL3-m6A-miR-338-3p axis.
• METTL3 inhibition presents a promising therapeutic avenue for IDD.
• Development of biomaterial delivery systems for METTL3 inhibitors is recommended for future therapeutic applications.