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

Abstract

Sensory 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.

Elucidating the Interactome of G Protein-Coupled Receptors and Receptor Activity-Modifying Proteins

“…Interestingly, CALCRL-RAMP1 has been shown to have mechanoresponsive properties and is involved in mechanical force transduction in macrophages in mice, thereby pointing to a role for RAMP1 in innate immunity ( Muschter et al, 2019 ). A role for RAMP1 in CGRP sensory nerve regulation of chondroitin sulfate synthesis in the context of extracellular matrix homeostasis of intervertebral discs was also reported ( Hu et al, 2022 ). The precise mechanism for mechanical force transduction effects mediated by GPCR complexes remains to be elucidated.…”

Ferroptosis: A potential target for the intervention of intervertebral disc degeneration

“…Under normal circumstances, the components of the ECM in the IVD are continuously updated through anabolism and catabolism, and the cells in the IVD associated with ECM form a coordinated functional system ( 138 ). However, the imbalance of anabolic and catabolic activities might result in ECM degradation, which is a pathological characteristic of IVDD ( 139 ). ECM metabolism is modulated by iron overload and ferroptosis.…”

Bee Pollen Stimulated BMP2 and RANK Signaling Pathway in Osteoprogenitors and Improved Bone Mineralization in Rat Model of Femur Fracture

“…ab83369), were measured using Abcam ELISA kits, similar to the method for measuring PTH and calcitonin hormone levels. The measurements were performed according to the manufacturer’s instructions and protocol (Hu et al, 2022).…”

“…ab236712) were measured using Abcam ELISA kits (Abcam Company, USA). The measurements were performed in a similar manner to the method for measuring PTH and calcitonin hormone levels, following the manufacturer's instructions and protocol (Hu et al, 2022).…”

“…No. MAB-4614) hormones were measured using commercial Novus enzyme-linked immunosorbent assay (ELISA) kits (Novus Biologicals, USA) based on a colorimetric assay, following the manufacturer's recommendations and protocol (Hu et al, 2022).…”