transforming-growth-factor-beta and Carpal-Tunnel-Syndrome

Carpal tunnel syndrome (CTS) is an entrapment neuropathy caused by compression and irritation of the median nerve, which travels through the carpal tunnel in the wrist. Increased fibrosis is a hallmark of the development and pathology of CTS. Different growth factors have been demonstrated to play a potential role in the development of CTS. Studies have described an increase in the expression of growth factors, including Transforming Growth Factor (TGF-β), Vascular Endothelial Growth Factor (VEGF) and interleukins (growth factors for immune and inflammatory cells) in SSCT (sub-synovial connective tissue) in CTS patients. Additionally, SSCT fibrosis is also marked by increased activation of canonical TGF-β second messenger Smads, increased expression of downstream fibrotic mediators such as connective tissue growth factor (CTGF), increased production of collagen type I, II, III and IV, and decreased expression of matrix metalloproteinases. Anti-fibrotic such as anti-TGF treatment may prove beneficial in idiopathic patients, however, anti VEGF therapy can be successful in the diabetic CTS patients. The present review describes the clinical evidence stating the role of different growth factors in the development of fibrosis in idiopathic and diabetes induced CTS.

Topics: Carpal Tunnel Syndrome; Connective Tissue Growth Factor; Diabetes Complications; Fibrosis; Humans; Intercellular Signaling Peptides and Proteins; Interleukins; Nerve Growth Factor; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A

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.

Topics: Carpal Tunnel Syndrome; Cells, Cultured; Collagen Type I; Collagen Type III; Connective Tissue; Connective Tissue Cells; Connective Tissue Growth Factor; ErbB Receptors; Fibroblasts; Fibrosis; Humans; Plasminogen Activator Inhibitor 1; Receptors, Platelet-Derived Growth Factor; Receptors, Transforming Growth Factor beta; Receptors, Vascular Endothelial Growth Factor; Synovial Membrane; Transforming Growth Factor beta

Lysyl oxidase (LO) is produced by myofibroblast cells in some tissues and can be influenced by transforming growth factor beta 1 (TGF beta 1). Myofibroblast-like cells are present in the flexor reticulum of patients with carpal tunnel syndrome (CTS). The goal of the current study was to determine LO activity and the effects of TGF beta 1 on LO expression in the cells from patients with CTS. Tissues from both hands of five individuals with CTS were used for this study. LO activity with and without TGF beta 1 stimulation was assayed in 7-day cell culture specimens. A significant difference in LO activity among individual patients, but not between right and left hands of the same patient, was observed. There was no correlation between the severity of CTS determined by nerve conduction studies and LO activity. Addition of TGF beta 1 significantly increased LO in all cell lines.

Topics: Adult; Aged; Aged, 80 and over; Analysis of Variance; Carpal Tunnel Syndrome; Cells, Cultured; Female; Humans; Male; Middle Aged; Muscle, Skeletal; Neural Conduction; Probability; Protein-Lysine 6-Oxidase; Sensitivity and Specificity; Severity of Illness Index; Transforming Growth Factor beta

Carpal Tunnel Syndrome (CTS) is an idiopathic fibrotic disorder. Fibrosis in the subsynovial connective tissues (SSCT) of CTS and many other fibrotic diseases is mediated by Transforming growth factor β (TGF-β). Recently monocyte chemoattractant protein-1 (MCP-1) a cytokine involved in cellular recruitment has been suggested to regulate TGF-β activity. It is related to the onset of diseases which are caused by fibrosis, such as idiopathic pulmonary fibrosis, renal fibrosis, and systemic scleroderma. In this study, we evaluated the effect of the MCP-1 synthesis inhibitor, Bindarit, on primary cultures of fibroblasts from the SSCT of five CTS patients.. Fibroblasts were treated with Bindarit (10 μM, 50 μM, 100 μM, or 300 μM). Responses to inhibitors were evaluated by regulation of CTS fibrosis-associated genes, fibrosis gene array and Smad luciferase reporter assay. We also assessed the combination effect of Bindarit and SD208, a TGF-β receptor type 1 inhibitor on TGF-β signaling.. Collagen type III A1 (Col3), connective tissue growth factor (CTGF), and SERPINE1 expression were significantly down-regulated by Bindarit (300 μM) compared to vehicle control. In the fibrosis array, expression of inhibin beta E chain precursor (INHBE), beta actin (ACTB), endothelin 1 (EDN1) and hypoxanthine phosphoribosyltransferase 1 (HPRT1) were significantly down-regulated, and integrin beta-3 (ITGB3) was significantly up-regulated by Bindarit (300 μM). Smad signal transduction activation was significantly down-regulated by Bindarit (300 μM) and/or SD208 (1 μM) with TGF-β1 compared to vehicle control with TGF-β1.. These results suggest that Bindarit in combination with SD208 may be beneficial as medical therapy for the SSCT fibrosis associated with CTS.

Topics: Carpal Tunnel Syndrome; Chemokine CCL2; Collagen Type III; Fibroblasts; Fibrosis; Humans; Transforming Growth Factor beta; Transforming Growth Factor beta1

Topics: Aged; Carpal Tunnel Syndrome; Collagen Type I; Collagen Type I, alpha 1 Chain; Collagen Type III; Estradiol; Estrogen Receptor alpha; Estrogen Receptor beta; Female; Fibroblasts; Fibrosis; Gene Expression Regulation, Developmental; Humans; Middle Aged; Postmenopause; Signal Transduction; Synovial Membrane; Transforming Growth Factor beta

Fibroblast behavior and cell-matrix interactions of cells from normal and idiopathic carpal tunnel syndrome (CTS) subsynovial connective tissue (SSCT) with and without Triamcinolone Acetonide (TA) were compared in this study. A cell-seeded gel contraction model was applied to investigate the effect of steroid treatment on SSCT fibroblast gene expression and function.. TA-treated gels had a significantly higher contraction rate, tensile strength and stiffness than the untreated gels. Proteinases involved in remodeling had increased expression in TA-treated gels of the patient group. Pro-fibrotic genes and ECM regulators, such as TGF-β, collagens and integrins, were down-regulated by TA, indicating that TA may work in part by decreasing fibrotic gene expression.. This study showed that TA affects cell-matrix interaction and suppresses fibrotic gene expression in the SSCT cells of CTS patients.

Topics: Carpal Tunnel Syndrome; Collagen; Female; Fibroblasts; Glucocorticoids; Humans; Male; Middle Aged; Polymerase Chain Reaction; Primary Cell Culture; Transforming Growth Factor beta; Triamcinolone Acetonide

The aim of this study was to investigate the anti-fibrotic effect of relaxin in subsynovial fibroblasts activated by transforming growth factor beta (TGF-β).. To test the anti-fibrotic effect of an adenovirus-relaxin construct (Ad-RLN) on subsynovial fibroblasts in vitro, cells from subsynovial connective tissue of patients with carpal tunnel syndrome were activated with TGF-β1 and exposed to Ad-RLN (as a therapeutic gene) or adenovirus-lacZ construct (as a marker gene) for four hours. Subsynovial fibroblast cultures without adenoviral exposure served as controls.. We observed induction of gene expressions of collagen I, III and IV, as well as the abatement of alpha-smooth muscle actin (a-SMA) synthesis, Smad2 phosphorylation, and fibronectin at the protein level, in comparison to controls. In addition, protein expressions of matrix metalloproteinase (MMP) I was significantly induced, whereas the protein expressions of tissue inhibitor of metalloproteinases (TIMP) I and IV were reduced due to relaxin expression.. RLN prevents excessive synthesis of extracellular matrix by reducing the expressions of its components, such as fibronectin, a-SMA, and phosphorylated Smad2, by increasing the expression of MMPs; and by decreasing the expression of TIMPs.

Topics: Carpal Tunnel Syndrome; Cells, Cultured; Collagen Type I; Collagen Type III; Collagen Type IV; Extracellular Matrix; Fibroblasts; Fibronectins; Humans; Matrix Metalloproteinases; Relaxin; Smad2 Protein; Tissue Inhibitor of Metalloproteinases; Transforming Growth Factor beta; Transforming Growth Factor beta1

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. Twofold 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.

Topics: Adult; Biopsy; Cadaver; Carpal Tunnel Syndrome; Collagen Type I; Collagen Type III; Connective Tissue Growth Factor; Fibroblasts; Fibrosis; Gene Expression Regulation; Humans; Middle Aged; Oligonucleotide Array Sequence Analysis; Pteridines; Signal Transduction; Smad3 Protein; Transforming Growth Factor beta

Topics: Carpal Tunnel Syndrome; Gene Expression Regulation; Immunosuppressive Agents; NF-kappa B; Nucleic Acid Synthesis Inhibitors; Oligopeptides; Protein Serine-Threonine Kinases; Receptor, Transforming Growth Factor-beta Type I; Receptors, Transforming Growth Factor beta; Rifampin; Smad2 Protein; Smad3 Protein; Transcription Factor AP-1; Transforming Growth Factor beta

The most common histological finding in carpal tunnel syndrome is noninflammatory synovial fibrosis. The accumulated effect of minor injuries is believed to be an important etiologic factor in some cases of carpal tunnel syndrome. We sought evidence of such injuries in the synovial tissue of patients with carpal tunnel syndrome and in cadaver controls.. We compared synovial specimens from thirty patients who had idiopathic carpal tunnel syndrome with specimens from a control group of ten fresh-frozen cadavers of individuals who had not had an antemortem diagnosis of carpal tunnel syndrome and who met the same exclusion criteria. Analysis included histological and immunohistochemical examination for the distribution of collagen types I, II, III, and VI and transforming growth factor-beta (TGF-beta) RI, RII, and RIII.. Histological examination showed a marked increase in fibroblast density, collagen fiber size, and vascular proliferation in the specimens from the patients compared with the control specimens (p < 0.001). Collagen types I and II were not found in the synovium of either the patients or the controls, but collagen type VI was a major component of both. Collagen type-III fibers were more abundant in the patients than in the controls (p < 0.001). Expression of TGF-beta RI was found in the endothelial cells and fibroblasts in the patient and control specimens, with a marked increase in expression in the fibroblasts of the patients compared with that in the control tissue (p < 0.001).. These findings are similar to those after injury to skin, tendon, and ligament and suggest that patients with idiopathic carpal tunnel syndrome may have sustained an injury to the subsynovial connective tissue.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Carpal Tunnel Syndrome; Child; Collagen; Connective Tissue; Female; Humans; Immunohistochemistry; Male; Middle Aged; Retrospective Studies; Synovial Membrane; Transforming Growth Factor beta

Dupuytren's contracture is a fibroproliferative disorder that is associated with increased collagen deposition. Isoforms of transforming growth factor beta (TGF(beta)), normally TGF(beta1) and TGF(beta2), are involved in the progressive fibrosis of Dupuytren's disease. It has been suggested that downregulation of TGF(beta) may be useful in the treatment of the condition. Tamoxifen, a synthetic nonsteroidal antiestrogen, is known to modulate the production of TGF(beta). This study examined the role of tamoxifen in decreasing fibroblast function and downregulating TGF(beta2).. Primary cultures of fibroblasts were obtained from Dupuytren's affected fascia and carpal tunnel affected fascia as a control. Collagen lattices were prepared and populated with the fibroblasts. The fibroblast-populated collagen lattices (FPCL) were then measured for contraction every 24 h for 5 days. Supernatant was obtained from the culture medium following completion of the FPCL portion of the experiment and used for a TGF(beta2) immunoassay.. Dupuytren's affected fibroblasts contracted the FPCLs significantly more than carpal tunnel control fibroblasts. Treating the fibroblasts with tamoxifen caused a decreased contraction rate in both Dupuytren's affected fibroblasts and carpal tunnel controls. There was increased TGF(beta2) expression in the Dupuytren's affected fascia group compared to the carpal tunnel control group. Tamoxifen decreased TGF(beta2) expression in Dupuytren's affected fascia group but not in the carpal tunnel control group.. TGF(beta) appears to be the key cytokine in the fibrogenic nature of Dupuytren's disease. Tamoxifen treatment has been demonstrated to decrease the function of fibroblasts derived from Dupuytren's affected fascia and downregulated TGF(beta2) production in these same fibroblasts. These data suggest a method to manipulate and control Dupuytren's contracture in the clinical setting.

Topics: Carpal Tunnel Syndrome; Cell Culture Techniques; Collagen; Dupuytren Contracture; Estrogen Antagonists; Fascia; Fibroblasts; Humans; Immunoassay; Tamoxifen; Transforming Growth Factor beta; Transforming Growth Factor beta2