Transthyretin Amyloid May Drive Fibrosis and Proliferation of Tenosynovial Fibroblasts in Carpal Tunnel Syndrome

Background: Transthyretin (TTR) amyloid deposition in the tenosynovium in carpal tunnel syndrome (CTS) is a potential early manifestation of systemic amyloidosis. However, its effects on tenosynovial fibroblasts in CTS remain unclear. We aimed to clarify how wild-type and Val30Met mutant TTR amyloids affect tenosynovial fibroblasts in CTS. Methods: Synovial tissue from 20 patients undergoing carpal tunnel release surgery was evaluated for TTR amyloid. Expression of genes related to fibrosis, inflammation, and oxidative stress was compared between TTR-positive and TTR-negative groups. Fibroblasts isolated from TTR-negative patients were treated in vitro with wild-type or Val30Met mutant recombinant TTR. Analyses included quantitative RT-PCR (reverse transcription-polymerase chain reaction), Picrosirius Red staining, MTT assays evaluating cell proliferation, reactive oxygen species (ROS) activity measurements, and senescence-related gene expression. Results: In TTR-positive tissue, fibrosis-related genes ( COL1A1, COL3A1, TGFB1, and ACTA2 ), the inflammatory mediator NFKB1 , and oxidative-stress-related genes ( KEAP1, NQO1, and SOD1 ) were significantly upregulated, whereas SOD2 was downregulated. With in vitro treatment in the TTR-negative group, both wild-type and Val30Met TTR increased COL3A1, IL6, and CXCL8 expression, whereas Val30Met TTR further enhanced IL1B expression. Picrosirius Red staining confirmed increased collagen deposition. MTT assays revealed increased cell viability, indicating enhanced fibroblast proliferation, in both groups. The senescence-related genes CDKN2D and GADD45A were downregulated, suggesting enhanced proliferative activity. ROS activity did not differ significantly between groups. Conclusions: TTR amyloid was found to promote expression of fibrosis, inflammation, and oxidative-stress-related genes; inhibit senescence pathways; and enhance collagen deposition and fibroblast proliferation in fibroblasts from patients with CTS. Clinical Relevance: CTS with TTR deposition may reflect more than a localized neuropathy, as TTR potentially plays a pathogenic role in CTS development. This finding provides novel insights into the underlying mechanisms of CTS.