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

• DOI: 10.1002/advs.202202620
• Publication Date: 2022-09-01T11:27:46Z
• Authors: Bo Hu; Xiao Lv; Leixin Wei; Yunhao Wang; Genjiang Zheng; Chen Yang; Fazhi Zang; Jianxi Wang; Jing Li; Xiaodong Wu; Zhihao Yue; Qiangqiang Xiao; Zengwu Shao; Wen Yuan; Jinsong Li; Peng Cao; Chen Xu; Huajiang Chen
• Keywords: 0303 health sciences; intervertebral disc degeneration; sensory nerves; nucleus pulposus; Science; Calcitonin Gene-Related Peptide; Q; Colforsin; Intervertebral Disc Degeneration; Extracellular Matrix; Receptor Activity-Modifying Protein 1; Mice; 03 medical and health sciences; Animals; Homeostasis; N-Acetylgalactosaminyltransferases; Glucuronosyltransferase; Cyclic AMP Response Element-Binding Protein; Intervertebral Disc; Research Articles; chondroitin sulfate; chondroitin sulfate synthase 1; Receptors, Calcitonin Gene-Related Peptide

AbstractSensory nerves are long being recognized as collecting units of various outer stimuli; recent advances indicate that the sensory nerve also plays pivotal roles in maintaining organ homeostasis. Here, this study shows that sensory nerve orchestrates intervertebral disc (IVD) homeostasis by regulating its extracellular matrix (ECM) metabolism. Specifically, genetical sensory denervation of IVD results in loss of IVD water preserve molecule chondroitin sulfate (CS), the reduction of CS bio‐synthesis gene chondroitin sulfate synthase 1 (CHSY1) expression, and dysregulated ECM homeostasis of IVD. Particularly, knockdown of sensory neuros calcitonin gene‐related peptide (CGRP) expression induces similar ECM metabolic disorder compared to sensory nerve denervation model, and this effect is abolished in CHSY1 knockout mice. Furthermore, in vitro evidence shows that CGRP regulates nucleus pulposus cell CHSY1 expression and CS synthesis via CGRP receptor component receptor activity‐modifying protein 1 (RAMP1) and cyclic AMP response element‐binding protein (CREB) signaling. Therapeutically, local injection of forskolin significantly attenuates IVD degeneration progression in mouse annulus fibrosus puncture model. Overall, these results indicate that sensory nerve maintains IVD ECM homeostasis via CGRP/CHSY1 axis and promotes IVD repair, and this expands the understanding concerning how IVD links to sensory nerve system, thus shedding light on future development of novel therapeutical strategy to IVD degeneration.