Tamoxifen, a synthetic nonsteroidal anti-estrogen known to modulate the production of transforming growth factor-beta (TGF-β), has demonstrated effectiveness on fibroblast activity in vitro and in vivo. The main purpose of this study was to investigate the effect of tamoxifen on the outcome of surgery for Dupuytren contractures in patients with a strong predisposition toward fibrosis.
We used a prospective, randomized, double-blind study protocol (conforming to the CONSORT standards) to investigate the influence of tamoxifen compared with placebo on the total passive extension deficit in the finger and patient satisfaction after subtotal fasciectomy in thirty patients with a strong predisposition toward fibrosis (grade, >4 according to the Abe scale). High-dosage tamoxifen (80 mg/day) was administered from six weeks prior until twelve weeks after surgery, and patients were monitored for two years.
Three months after surgery, patients in the tamoxifen group had a smaller total passive extension deficit and higher satisfaction compared with the placebo group. This positive effect was lost over the two years following cessation of the medication.
This study demonstrated that the short-term outcome of Dupuytren disease treatment could be influenced by use of tamoxifen as a neoadjuvant from six weeks prior to three months after subtotal fasciectomy in patients with a strong predisposition toward fibrosis. However, the beneficial effect disappeared within two years after surgery, with worsening of the contractures after the medication was discontinued. Thus, tamoxifen may have a short-term effect on the outcome of surgery for Dupuytren disease.
Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.
"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., 2014; Kim et al., 2014; Yoldas et al., 2015). "
[Show abstract][Hide abstract] ABSTRACT: 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. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
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