title: Blocking fibrotic signaling in fibroblasts from patients with carpal tunnel syndrome.
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.
authors.affiliation: Biomechanics and Tendon & Soft Tissue Biology Laboratory, Department of Orthopedic Surgery, Mayo Clinic, Rochester, Minnesota.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Yamanaka
authors.affiliation: Biomechanics and Tendon & Soft Tissue Biology Laboratory, Department of Orthopedic Surgery, Mayo Clinic, Rochester, Minnesota.
authors.forename: Anne
authors.initials: A
authors.lastname: Gingery
authors.affiliation: Biomechanics and Tendon & Soft Tissue Biology Laboratory, Department of Orthopedic Surgery, Mayo Clinic, Rochester, Minnesota.
authors.forename: Gosuke
authors.initials: G
authors.lastname: Oki
authors.affiliation: Biomechanics and Tendon & Soft Tissue Biology Laboratory, Department of Orthopedic Surgery, Mayo Clinic, Rochester, Minnesota.
authors.forename: Tai-Hua
authors.initials: TH
authors.lastname: Yang
authors.affiliation: Biomechanics and Tendon & Soft Tissue Biology Laboratory, Department of Orthopedic Surgery, Mayo Clinic, Rochester, Minnesota.
authors.forename: Chunfeng
authors.initials: C
authors.lastname: Zhao
authors.affiliation: Biomechanics and Tendon & Soft Tissue Biology Laboratory, Department of Orthopedic Surgery, Mayo Clinic, Rochester, Minnesota.
authors.forename: Peter C
authors.identifier: http://orcid.org/0000-0002-2206-4772
authors.initials: PC
authors.lastname: Amadio
mesh_terms: D002349:Carpal Tunnel Syndrome / Q000188:drug therapy* / Q000473:pathology; D002478:Cells, Cultured; D024042:Collagen Type I / Q000096:biosynthesis / Q000235:genetics; D024061:Collagen Type III / Q000096:biosynthesis / Q000235:genetics; D003238:Connective Tissue / Q000473:pathology; D003239:Connective Tissue Cells / Q000166:cytology; D055513:Connective Tissue Growth Factor / Q000096:biosynthesis / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005347:Fibroblasts / Q000378:metabolism; D005355:Fibrosis / Q000188:drug therapy / Q000473:pathology*; D006801:Humans; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis / Q000235:genetics; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors*; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D013583:Synovial Membrane / Q000166:cytology / Q000473:pathology*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: C526317:CCN2 protein, human; C439971:COL3A1 protein, human; D024042:Collagen Type I; D024061:Collagen Type III; D017395:Plasminogen Activator Inhibitor 1; D018125:Receptors, Transforming Growth Factor beta; C051321:SERPINE1 protein, human; D016212:Transforming Growth Factor beta; D055513:Connective Tissue Growth Factor; C512478:EGFR protein, human; D066246:ErbB Receptors; D017479:Receptors, Platelet-Derived Growth Factor; D040262:Receptors, Vascular Endothelial Growth Factor
keywords: carpal tunnel syndrome; fibrosis; subsynovial connective tissue; transforming growth factor β