Blocking fibrotic signaling in fibroblasts from patients with carpal tunnel syndrome

Yoshiaki Yamanaka, Anne Gingery, Gosuke Oki, Tai-Hua Yang, Chunfeng Zhao, Peter C. Amadio

Research output: Contribution to journalReview article

5 Citations (Scopus)

Abstract

Fibrosis of the subsynovial connective tissue (SSCT) in carpal tunnel syndrome (CTS) patients is increasingly recognized as an important aspect of CTS pathophysiology. In this study, we evaluated the effect of blocking profibrotic pathways in fibroblasts from the SSCT in CTS patients. Fibroblasts were stimulated with transforming growth factor β1 (TGF-β1), and then treated either with a specific fibrosis pathway inhibitor targeting TGF-β receptor type 1 (TβRI), platelet-derived growth factor receptor (PDGFR), epidermal growth factor receptor (EGFR), or vascular endothelial growth factor receptor (VEGFR). Fibrosis array and quantitative real-time polymerase chain reaction of fibrotic genes were evaluated. Array gene expression analysis revealed significant down-regulation of multiple fibrotic genes after treatment with TβRI, PDGFR, and VEGFR inhibitors. No array fibrotic genes were significantly down-regulated with EGFR inhibition. Further gene expression analysis of known CTS fibrosis markers collagen type I A2 (Col1), collagen type III A1 (Col3), connective tissue growth factor (CTGF), and SERPINE1 showed significantly down-regulation after TβRI inhibition. In contrast, VEGFR inhibition significantly down-regulated CTGF and SERPINE1, whereas, PDGFR and EGFR inhibition significantly down-regulated Col3. Taken together the inhibition of TβRI appears to be the primary mediator of fibrotic gene expression in fibroblasts from CTS patients. TGF-β/Smad activity was further evaluated, and as expected inhibition of Smad activity was significantly down-regulated after inhibition of TβRI, but not with PDGFR, VEGFR, or EGFR inhibition. These results indicate that local therapies specifically targeting TGF-β signaling alone or in combination offer the potential of a novel local antifibrosis therapy for patients with CTS.

Original languageEnglish
Pages (from-to)2067-2074
Number of pages8
JournalJournal of Cellular Physiology
Volume233
Issue number3
DOIs
Publication statusPublished - 2018 Mar 1

Fingerprint

Carpal Tunnel Syndrome
Fibroblasts
Platelet-Derived Growth Factor Receptors
Tunnels
Vascular Endothelial Growth Factor Receptor
Epidermal Growth Factor Receptor
Fibrosis
Gene expression
Connective Tissue Growth Factor
Genes
Gene Expression
Connective Tissue
Down-Regulation
Tissue
Collagen Type III
Polymerase chain reaction
Transforming Growth Factors
Collagen Type I
varespladib methyl
Real-Time Polymerase Chain Reaction

All Science Journal Classification (ASJC) codes

  • Physiology
  • Clinical Biochemistry
  • Cell Biology

Cite this

Yamanaka, Yoshiaki ; Gingery, Anne ; Oki, Gosuke ; Yang, Tai-Hua ; Zhao, Chunfeng ; Amadio, Peter C. / Blocking fibrotic signaling in fibroblasts from patients with carpal tunnel syndrome. In: Journal of Cellular Physiology. 2018 ; Vol. 233, No. 3. pp. 2067-2074.
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abstract = "Fibrosis of the subsynovial connective tissue (SSCT) in carpal tunnel syndrome (CTS) patients is increasingly recognized as an important aspect of CTS pathophysiology. In this study, we evaluated the effect of blocking profibrotic pathways in fibroblasts from the SSCT in CTS patients. Fibroblasts were stimulated with transforming growth factor β1 (TGF-β1), and then treated either with a specific fibrosis pathway inhibitor targeting TGF-β receptor type 1 (TβRI), platelet-derived growth factor receptor (PDGFR), epidermal growth factor receptor (EGFR), or vascular endothelial growth factor receptor (VEGFR). Fibrosis array and quantitative real-time polymerase chain reaction of fibrotic genes were evaluated. Array gene expression analysis revealed significant down-regulation of multiple fibrotic genes after treatment with TβRI, PDGFR, and VEGFR inhibitors. No array fibrotic genes were significantly down-regulated with EGFR inhibition. Further gene expression analysis of known CTS fibrosis markers collagen type I A2 (Col1), collagen type III A1 (Col3), connective tissue growth factor (CTGF), and SERPINE1 showed significantly down-regulation after TβRI inhibition. In contrast, VEGFR inhibition significantly down-regulated CTGF and SERPINE1, whereas, PDGFR and EGFR inhibition significantly down-regulated Col3. Taken together the inhibition of TβRI appears to be the primary mediator of fibrotic gene expression in fibroblasts from CTS patients. TGF-β/Smad activity was further evaluated, and as expected inhibition of Smad activity was significantly down-regulated after inhibition of TβRI, but not with PDGFR, VEGFR, or EGFR inhibition. These results indicate that local therapies specifically targeting TGF-β signaling alone or in combination offer the potential of a novel local antifibrosis therapy for patients with CTS.",
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Blocking fibrotic signaling in fibroblasts from patients with carpal tunnel syndrome. / Yamanaka, Yoshiaki; Gingery, Anne; Oki, Gosuke; Yang, Tai-Hua; Zhao, Chunfeng; Amadio, Peter C.

In: Journal of Cellular Physiology, Vol. 233, No. 3, 01.03.2018, p. 2067-2074.

Research output: Contribution to journalReview article

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AU - Yamanaka, Yoshiaki

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AU - Oki, Gosuke

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AU - Amadio, Peter C.

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