Abstract
Dupuytren's disease (DD) is a fibroproliferative disorder of the palmar aponeurosis, which is characterized by a compound myofibrogenesis and evidenced by an increased expression of α-smooth muscle actin (α-SMA). In Dupuytren's tissue, higher levels of reactive oxygen species (ROS) are documented, stimulating the proliferation and differentiation of myofibroblasts. Our preliminary study demonstrates that α-SMA-expression is significantly inhibited by blue light irradiation in DD. The objective of this study was to investigate the beneficial effect of blue light irradiation and to elucidate the influence of ROS on myofibrogenesis in the pathogenesis of DD. Therefore, an in-vitro model of human DD fibroblasts was used. DD fibroblasts and control fibroblasts isolated from carpal tunnel syndrome (CTS) were daily irradiated with 40 J/cm2 (λ = 453 nm, 38 mW/cm2). Protein expression of ROS-modulating enzymes (Catalase, NOX4, SOD1, MnSOD) and α-SMA were determined, and additionally analysed after a pharmacological inhibition of the TGF-β1-signaling with SB431542. Furthermore, the protein expression of α-SMA as surrogate parameter for myofibrogenesis was evaluated after applying different concentrations of long-lasting ROS. It could be determined that the beneficial blue light irradiation, which inhibited myofibrogenesis, is mediated by a significant inhibition of catalase protein expression. This effect should be accompanied with an increased intracellular ROS level. Proof of evidence was an H2O2-application on DD fibroblasts, also leading to a decreased myofibrogenesis. Furthermore, it could be demonstrated that endogenous MnSOD was significantly downregulated in resting DD fibroblasts. If DD fibroblasts were treated with the pharmacological inhibitor SB431542, myofibrogenesis was inhibited, but MnSOD expression was simultaneously elevated, which ought to affect ROS level by raising intracellular H2O2 amount. Blue light irradiation as well as the pharmacological action of SB431542 in consequence mediates their beneficial effect on disturbed myofibrogenesis in DD by further increasing ROS level. The present study demonstrates the importance of intracellular ROS homeostasis in DD and illuminates the beneficial effect of blue light as a promising therapy option for DD.
Highlights
Dupuytren’s disease (DD) is a fibroproliferative disorder of the palmar fascia of the hand that often leads to disabling flexion contracture of the affected fingers
Data obtained from respective carpal tunnel syndrome (CTS) figures were only shown or discussed, if the CTS data were significantly different to DD data
Blue light irradiation did not affect NOX4 protein expression in DD fibroblast (Fig 2E and 2F), there was a slight effect on day 3 in transforming growth factor-β 1 (TGF-β1) treated DD fibroblasts (Fig 2E)
Summary
Dupuytren’s disease (DD) is a fibroproliferative disorder of the palmar fascia of the hand that often leads to disabling flexion contracture of the affected fingers. Preliminary studies confirmed that transforming growth factor-β 1 (TGF-β1), a potent pro-fibrogenic cytokine abundant in DD, induces myofibroblast proliferation and differentiation with significant higher α-SMA expression [9]. It is known that TGFβ1 increases ROS production and suppresses antioxidant enzymes, thereby inducing redox imbalance, which contributes to fibrosis [10]. A redox imbalance in favor of ROS, called oxidative stress, causes undirected cell damage through oxidation of macromolecules, such as proteins or DNA and RNA, frequently inducing deleterious damage and apoptosis in cells [11,12,13]. Oxidative stress is related in the pathogenesis of many diseases like cancer, diabetes mellitus, atherosclerosis, as well as in aging and tissue fibrosis [14,15,16]. Catalase in turn promotes the conversion from H2O2 into H2O
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