TRPC6-Mediated Ca2+ Influx Activates MAPK and NFκB Signaling and Elicits Pro-Inflammatory and Catabolic Responses in Human Intervertebral Disc Cells

TL;DR

TRPC6 activation in disc cells causes calcium influx, leading to inflammation and tissue breakdown, suggesting it could be a new target for treating back pain.

Contribution

This study identifies TRPC6 as a novel upstream regulator linking calcium signaling to disc degeneration processes.

Findings

TRPC6 activation in human disc cells triggers MAPK and NF-κB signaling pathways.

TRPC6 activation increases expression of inflammatory and catabolic markers like IL-6, IL-8, and MMPs.

Pharmacological targeting of TRPC6 may suppress inflammation and matrix degradation in degenerative disc disease.

Abstract

What are the main findings?
TRPC6 is endogenously expressed in human intervertebral disc cells, and its activation induces rapid calcium influx that initiates MAPK and NF-κB signaling pathways.TRPC6 activation initiates a broad inflammatory and degenerative program, elevating the expression of IL-6, IL-8, COX-2, MMP-1, MMP-3, NGF, and VEGF.

TRPC6 is endogenously expressed in human intervertebral disc cells, and its activation induces rapid calcium influx that initiates MAPK and NF-κB signaling pathways.

TRPC6 activation initiates a broad inflammatory and degenerative program, elevating the expression of IL-6, IL-8, COX-2, MMP-1, MMP-3, NGF, and VEGF.

What are the implications of the main findings?
TRPC6 functions as a key upstream regulator linking calcium influx with inflammatory, matrix-degrading, and neuro-angiogenic processes central to disc degeneration and discogenic back pain.Pharmacological targeting of TRPC6 may offer a novel therapeutic approach to suppress early inflammatory signaling, limit extracellular matrix breakdown, and reduce neurovascular ingrowth in degenerative disc disease.

TRPC6 functions as a key upstream regulator linking calcium influx with inflammatory, matrix-degrading, and neuro-angiogenic processes central to disc degeneration and discogenic back pain.

Pharmacological targeting of TRPC6 may offer a novel therapeutic approach to suppress early inflammatory signaling, limit extracellular matrix breakdown, and reduce neurovascular ingrowth in degenerative disc disease.

Intervertebral disc degeneration is characterized by inflammation, extracellular matrix breakdown, and neurovascular ingrowth, processes that contribute to discogenic, chronic back pain. The transient receptor potential canonical 6 (TRPC6) channel is a calcium-permeable ion channel implicated in inflammation and pain signaling in multiple tissues; however, its functional role in human disc cells remain unknown. Here, we investigated the expression, activation, and downstream consequences of TRPC6 activation using Hyp9, a pharmacological activator of TRPC6. TRPC6 transcripts were consistently detected across all donors examined (n = 17). Functional TRPC6 activation induced a rapid, dose-dependent calcium (Ca2+) influx across 0.5–100 µM Hyp9. TRPC6 activation did not reduce metabolic activity or increase cytotoxicity at concentrations commonly used for in vitro TRPC6 activation. Mechanistically, TRPC6 activation induced mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) pathways, as demonstrated by increased phosphorylation of p38 and extracellular signal-regulated kinase (ERK), degradation of the inhibitor of κB-alpha (IκB-α), and increased nuclear translocation of the NF-κB p65 subunit. Downstream of these early signaling events, TRPC6 activation elicited a robust inflammatory and catabolic response with upregulation of IL-6, IL-8, COX-2, MMP-1, MMP-3, NGF, and VEGF, with corresponding increases in protein secretion. These findings identify TRPC6 as an important signaling node linking calcium influx to inflammatory, catabolic, and neuro- and angiogenesis-associated pathways in disc cells, highlighting TRPC6 as a potential therapeutic target in degenerative disc disease.

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