Dupuytren's contracture (DC) is an inflammatory fibrosis characterized by fibroproliferative disorders of the palmar aponeurosis, for which there is no effective treatment. Although several genome-wide association studies have identified risk alleles associated with DC, the functional linkage between these alleles and the pathogenesis remains elusive. We here focused on two single nucleotide polymorphisms (SNPs) associated with DC, rs16879765 and rs17171229, in secreted frizzled related protein 4 (SFRP4). We investigated the association of SRFP4 with the IL-6 amplifier, which amplifies the production of IL-6, growth factors and chemokines in non-immune cells and aggravates inflammatory diseases via NF-κB enhancement. Knockdown of SFRP4 suppressed activation of the IL-6 amplifier in vitro and in vivo, whereas the overexpression of SFRP4 induced the activation of NF-κB-mediated transcription activity. Mechanistically, SFRP4 induced NF-κB activation by directly binding to molecules of the ubiquitination SFC complex, such as IkBα and βTrCP, followed by IkBα degradation. Furthermore, SFRP4 expression was significantly increased in fibroblasts derived from DC patients bearing the risk alleles. Consistently, fibroblasts with the risk alleles enhanced activation of the IL-6 amplifier. These findings indicate that the IL-6 amplifier is involved in the pathogenesis of DC, particularly in patients harboring the SFRP4 risk alleles. Therefore, SFRP4 is a potential therapeutic target for various inflammatory diseases and disorders, including DC.

中文翻译：

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Dupuytren 挛缩相关的 SNP 会增加非免疫细胞（包括成纤维细胞）中 SFRP4 的表达，从而促进炎症发展。

掌腱膜挛缩症 (DC) 是一种以掌腱膜纤维增生性疾病为特征的炎性纤维化，目前尚无有效的治疗方法。尽管一些全基因组关联研究已经确定了与 DC 相关的风险等位基因，但这些等位基因与发病机制之间的功能联系仍然难以捉摸。我们在这里重点关注分泌性卷曲相关蛋白 4 (SFRP4) 中与 DC 相关的两个单核苷酸多态性 (SNP)，rs16879765 和 rs17171229。我们研究了 SRFP4 与 IL-6 放大器的关联，IL-6 放大器会放大非免疫细胞中 IL-6、生长因子和趋化因子的产生，并通过 NF-κB 增强而加重炎症性疾病。SFRP4 的敲除抑制了 IL-6 放大器在体外和体内的激活，而 SFRP4 的过度表达则诱导 NF-κB 介导的转录活性的激活。从机制上讲，SFRP4 通过直接结合泛素化 SFC 复合物的分子（例如 IkBα 和 βTrCP）诱导 NF-κB 激活，然后降解 IkBα。此外，来自携带风险等位基因的 DC 患者的成纤维细胞中 SFRP4 表达显着增加。一致的是，具有风险等位基因的成纤维细胞增强了 IL-6 放大器的激活。这些发现表明 IL-6 放大器参与 DC 的发病机制，特别是在携带 SFRP4 风险等位基因的患者中。因此，SFRP4是包括DC在内的多种炎症性疾病和病症的潜在治疗靶点。