High-Dosage Tamoxifen as Neoadjuvant Treatment in Minimally Invasive Surgery for Dupuytren Disease in Patients with a Strong Predisposition Toward Fibrosis

Degreef, Ilse; Tejpar, Sabine; Sciot, Raf; Smet, Luc De

doi:10.2106/jbjs.l.01623

Cited by 26 publications

(15 citation statements)

References 38 publications

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“…Further, it would be worth exploring the potential benefits of tamoxifen in other cancers where activated fibroblasts are prominent. As mentioned above, many studies already point to tamoxifen having such an effect on activated fibroblasts in vivo in models of fibrosis (Degreef et al, ; Kim et al, ; Yoldas et al, ).…”

Section: Discussionmentioning

confidence: 97%

“…As activated myofibroblasts are the key effector cells of tissue fibrosis (Hinz et al, 2007), our data support a number of recent studies which have shown anti-fibrotic properties for tamoxifen. Tamoxifen has been shown to inhibit renal fibrosis (Lee et al, 2009;Delle et al, 2012), retroperitoneal fibrosis (Ozener et al, 1997;Huang et al, 2011;van Bommel et al, 2006), hypertrophic scarring (Mousavi et al, 2010) and Dupuytren disease (Degreef et al, 2014), as well as silicainduced lung fibrosis (Yoldas et al, 2015). In these studies, the effect of tamoxifen has been linked to a downregulation in the expression of TGF-b and other growth factors in affected tissues (Mikulec et al, 2001;Delle et al, 2012;Yoldas et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

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Tamoxifen Inhibits TGF‐β‐Mediated Activation of Myofibroblasts by Blocking Non‐Smad Signaling Through ERK1/2

Carthy

Sundqvist

Heldin

et al. 2015

Journal Cellular Physiology

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Transforming growth factor-β (TGF-β) is a multifunctional cytokine which stimulates the differentiation of fibroblasts into myofibroblasts. Myofibroblasts are critical for normal wound healing, but also accumulate pathologically in a number of chronic inflammatory conditions where they are key contributors to aberrant tissue remodeling and fibrosis, and in cancer stroma. In the current study, we identified a role for tamoxifen as a potent inhibitor of the TGF-β-mediated activation of primary human skin and breast fibroblasts. Our data indicate that tamoxifen does not interfere with canonical Smad signaling downstream of TGF-β but rather blocks non-Smad signaling through ERK1/2 MAP-kinase and the AP-1 transcription factor FRA2. We further demonstrate by siRNA-mediated knockdown that FRA2 is critical for the induced expression of myogenic proteins in response to TGF-β. Functionally, TGF-β-stimulated fibroblast-mediated contraction of collagen gels was impaired in the presence of tamoxifen. Altogether, these data demonstrate that tamoxifen prevents myofibroblast differentiation and, therefore, may provide therapeutic benefits to patients suffering from chronic inflammatory conditions or cancer.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Tamoxifen Inhibits TGF‐β‐Mediated Activation of Myofibroblasts by Blocking Non‐Smad Signaling Through ERK1/2

Carthy

Sundqvist

Heldin

et al. 2015

Journal Cellular Physiology

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“…Our hypothesis has already been partially developed. In a clinical assay, the oral administration of tamoxifen controlled the recurrence rate until the end of the treatment [13] after performing the fasciectomy. Other substances have been postulated for DC treatment and they could be successful under these conditions.…”

Section: Discussionmentioning

confidence: 99%

“…Spatial reorganization of the ECM is a crucial turning point for fibroblast activity [12]. This is one of the reasons why certain clinical assays (e.g., tamoxifen) did not produce the expected results [13] after in vitro assays provided promising outcomes [14].…”

Section: Problems With DC Researchmentioning

confidence: 99%

Prevention of Recurrences in Dupuytren’s Contracture: Are We in the Right Side?

Sanjuán-Cerveró

2019

SN Compr. Clin. Med.

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Dupuytren contracture is a fibroproliferative disorder affecting the palm of the hand causing a sustained flexion of the fingers due to fibrous cord contracture. Collagenase clostridium histolyticum, as pharmacological treatment, achieves the selective degradation of a portion of the cord, thus enabling the affected finger's functionality. Our hypothesis is based on a literary review looking for associations based on collagenase for the treatment of the Dupuytren's disease. Current treatment options for Dupuytren's are symptomatic and aim at removing part of the affected tissue to restore hand functionality. Recurrence remains the greatest challenge for achieving long-term successful treatment. The association of a hydrogel with the collagenase increases the action time of the latter. The association to a collagenase-hydrogel complex with a third drug (anti-TGFß) acting at the unstructured extracellular matrix in the proliferative phase of the response of wound healing that takes place after the administration of collagenase for direct action on the transformation of fibroblast into myofibroblast, thus resembling as far as possible the actions drugs have on cell cultures. However, in Dupuytren's contracture, the breakage and degradation of the cord that occur with current treatment make this increase in local action time unnecessary. Combining actual treatment options in Dupuytren's disease with a hydrogel acting as a vehicle can provide an alternative to destroy the extracellular matrix and act directly against the myofibroblast.

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“…The deterioration of joint contracture may drastically decrease the quality of life for patients as they eventually suffer from lifelong disability. Despite years of investigation by professionals involved in primary care and rehabilitation, the pathological factors leading to the aggravation and restriction of joint contracture remain to be elucidated [5,6].…”

Section: Introductionmentioning

confidence: 99%

Suppression of TGF-beta activity with remobilization attenuates immobilization-induced joint contracture in rats

Mao¹,

Mi²,

Pan³

et al. 2020

Preprint

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Background Joint contracture is a common complication of joint injury. This study aimed to assess the effect of inhibiting the transforming growth factor-β (TGF-β) signaling during joint immobilization and remobilization on immobilization-induced joint contracture in rats. Methods The knees of rats were immobilized using Kirschner wires following trauma to the femoral condyles to generate joint contracture. After immobilization, levels of TGF-β and passive extension range of motion (ROM) were measured at different time points, joints were histologically analyzed by hematoxylin and eosin (H&E) and Masson trichrome staining, and the expression of inflammatory or fibrosis-related mediators, including interleukin-1β (IL-1β), phosphorylated Smad2/3 (p-Smad2/3), α-smooth muscle actin (α-SMA) and collagen types I (Col 1) and III (Col 3), were examined in joint capsules using immunohistochemistry and quantitative real-time polymerase chain reaction (qRT-PCR). Rats were also treated with LY2157299, a TGF-β receptor I kinase inhibitor, at different stages of immobilization and remobilization. Results TGF-β1 levels in the serum and the number of p-Smad2/3+ cells in the joint capsule were significantly elevated after immobilization. ROM decreased during the 6 weeks of immobilization and partly recovered after remobilization. After treatment with LY2157299 during immobilization, the restricted ROM moderately increased, but this effect was stronger when combined with active motion. Mechanistically, the expression of IL-1β, TGF-β, fibrosis-related factors, and the density of collagen significantly decreased after treatment with LY2157299. Conclusions Inhibiting TGF-β signaling paired with active motion effectively attenuated the formation of immobilization-induced joint contracture in rats.

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High-Dosage Tamoxifen as Neoadjuvant Treatment in Minimally Invasive Surgery for Dupuytren Disease in Patients with a Strong Predisposition Toward Fibrosis

Cited by 26 publications

References 38 publications

Tamoxifen Inhibits TGF‐β‐Mediated Activation of Myofibroblasts by Blocking Non‐Smad Signaling Through ERK1/2

Tamoxifen Inhibits TGF‐β‐Mediated Activation of Myofibroblasts by Blocking Non‐Smad Signaling Through ERK1/2

Prevention of Recurrences in Dupuytren’s Contracture: Are We in the Right Side?

Suppression of TGF-beta activity with remobilization attenuates immobilization-induced joint contracture in rats

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