Abstract
Carpal tunnel syndrome (CTS), the most common entrapment neuropathy, is characterised by fibrosis and thickening of the subsynovial connective tissue (SSCT) surrounding the median nerve. Although traditionally considered “non-inflammatory,” emerging evidence indicates immune involvement, including elevated cytokines and T-lymphocyte infiltration within the SSCT. Insulin-like growth factor 1 (IGF-1) has been implicated as a potential driver of fibrosis in CTS. Genome-wide association studies identified rs62175241 as a shared risk locus for CTS and trigger finger, where the protective T allele upregulates the long non-coding RNA DIRC3 and its downstream target IGFBP5. Increased IGFBP5 suppresses IGF-1 signalling by binding the ligand, and in other fibrotic diseases has also been linked to T-cell regulation, suggesting a dual fibrotic and immunomodulatory role in CTS.
To investigate the link between fibrosis, inflammation, and the IGF-1 pathway in CTS, we performed bulk RNA-sequencing on SSCT from CTS patients stratified by genotype at the DIRC3 locus. Differential expression analysis of high-risk versus intermediate- and low-risk genotypes at the DIRC3 locus revealed 32 upregulated and 316 downregulated genes in high-risk individuals. Upregulated genes included metabolic regulators (ADIPOQ, GPD1, KLB), whereas downregulated genes encompassed immune mediators (CXCL11, MMP9, IL4I1).
Downregulated genes were enriched for pathways related to adaptive immune responses, including T-cell regulation, challenging the prevailing model of strictly non-inflammatory fibrosis. Furthermore, several components of the IGF axis (IGFBP5, IGFLR1, IGF2BP3) were downregulated in high-risk patients, supporting a role for IGF signalling in CTS. These findings provide evidence to support a model in which dysregulation of IGF-1 signalling intersects with adaptive immune responses to drive fibrosis in CTS, challenging the traditional view of the disease as purely non-inflammatory.
Competing Interest Statement
The authors have declared no competing interest.
Funding Statement
AW is supported by an Arthritis UK Career Development Fellowship (Award Reference 23208), and this work was supported by an MRC fellowship (MR/ N001524/1). DF is supported by the NIHR Biomedical Research Centre, Oxford. (Biomedical Research Centre). AS is supported by a Wellcome Trust Clinical Career Development Fellowship (222101/Z/20/Z) and the NIHR Oxford Biomedical Research Centre.
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The Oxford carpal tunnel syndrome cohort was derived from two clinical studies that were approved by the National Research Ethics Service (UK): the Pain in Neuropathy Study (PiNS; 10/H07056/35), and the Molecular Genetics of Carpal Tunnel Syndrome (MGCTS) study (16/LO/1920).
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