Sensory Nerve Maintains Intervertebral Disc Extracellular Matrix Homeostasis Via CGRP/CHSY1 Axis

Area of Science:

• Neuroscience
• Biochemistry
• Orthopedics

Background:

• Sensory nerves traditionally detect external stimuli.
• Emerging evidence highlights their role in maintaining organ homeostasis.
• The specific role of sensory nerves in intervertebral disc (IVD) health was previously unclear.

Purpose of the Study:

• To investigate the role of sensory nerves in regulating intervertebral disc (IVD) homeostasis.
• To elucidate the molecular mechanisms by which sensory nerves influence IVD extracellular matrix (ECM) metabolism.
• To explore potential therapeutic strategies for IVD degeneration targeting sensory nerve pathways.

Main Methods:

• Genetical sensory denervation in mice.
• Knockdown of calcitonin gene-related peptide (CGRP) expression.
• CHSY1 knockout mouse model.
• In vitro studies using nucleus pulposus cells.
• Forskolin injection in a mouse annulus fibrosus puncture model.

Main Results:

• Sensory denervation led to loss of chondroitin sulfate (CS) and reduced CHSY1 expression, disrupting IVD ECM homeostasis.
• CGRP knockdown mimicked denervation effects, which were abolished in CHSY1 knockout mice.
• CGRP signaling via RAMP1 and CREB regulates nucleus pulposus cell CHSY1 expression and CS synthesis.
• Forskolin treatment attenuated IVD degeneration in vivo.

Conclusions:

• Sensory nerves maintain IVD ECM homeostasis through the CGRP/CHSY1 axis.
• This pathway is critical for IVD repair and resilience.
• Understanding this neuro-disc connection offers new therapeutic avenues for IVD degeneration.