TGF‐β signaling regulates fibrotic expression and activity in carpal tunnel syndrome

Abstract

Fibrosis of the subsynovial connective tissue (SSCT) is a predominant feature of carpal tunnel syndrome (CTS). While the nature of CTS has been extensively studied, little is known about the etiology of this disease. We investigated SSCT tissue from patients with CTS and control subjects using fibrosis arrays and cell culture analysis. Two-fold changes in fibrotic gene expression were found in multiple genes from patient SSCT using fibrosis arrays. This data was confirmed via qRT-PCR on a subset of genes; collagen I (Col1), collagen III (Col3), connective tissue growth factor (CTGF), transforming growth factor β (TGF-β) and SMAD3 (p<0.05), which significantly corroborate the fold changes found in the fibrosis arrays. To further explore the nature of SSCT fibrosis, cells were isolated from patient and control tissue. Col1, Col3, TGF-β, and SMAD3 were highly expressed in patient SSCT fibroblasts as compared to control (p<0.05). Further, fibrotic genes expression was decreased by inhibiting TGF-β receptor I (TβRI) activity (p<0.05). TGF-β second messenger SMAD activity was significantly activated in SSCT fibroblasts from patients and this activation was abrogated by inhibiting TβRI signaling (p<0.05). These findings suggest that blocking TGF-β signaling may be an important therapeutic approach to treating the underlying fibrosis of SSCT in CTS patients.

Collagen gel contraction as a measure of fibroblast function in an animal model of subsynovial connective tissue fibrosis

“…6,28,32 The SSCT fibrosis in CTS is also marked by decreased matrix metalloproteases expression, an observation that fits with the increased fibrosis found in this tissue and a lack of normal matrix remodeling. 28,32-34 …”

“…6,28,29 In addition, this SSCT fibrosis is marked by increased TGF-b receptors, 6,30 increased activation of canonical TGF-b second messenger Smads, 28,31 increased expression of downstream fibrotic mediators such as CTGF, 28,29 and increased production of collagen types I, III, and VI. 6,28,32 The SSCT fibrosis in CTS is also marked by decreased matrix metalloproteases expression, an observation that fits with the increased fibrosis found in this tissue and a lack of normal matrix remodeling. 28,[32][33][34] In this study, we explored the ability of fibrotic SSCT cells to contract a collagen gel matrix.…”

Collagen gel contraction as a measure of fibroblast function in carpal tunnel syndrome

“…Third, we did not assess the fibrotic phenotype of our cells after passage. However, in a parallel project, we have shown that a fibrotic phenotype is maintained after up to five passages in the CTS‐derived cells. Future work will explore biological mechanisms of action evaluating differences in gene expression, matrix organization, and interaction with cells and matrix degradation.…”

PFN2 and GAMT as common molecular determinants of axonal Charcot-Marie-Tooth disease

“…The F18 patient also had an additional carpal tunnel syndrome, which has been shown to upregulate several proteins including actin-binding proteins,19 thus possibly explaining why we did not observe the change. However, for GDAP1 mutations, the results were individual-specific (F26) as other GDAP1 patients recruited in the extended cohort clearly exhibited the decrease in PFN2 and GAMT.…”