PDF(Pubmed)
Abstract：
Wnt signaling is critically involved in fracture healing. Existing data predominantly relies on rodent models. Here, we explored local and circulating Dickkopf-1 (DKK1) levels in patients with respect to fracture healing and explore its association to sclerostin (SOST). 69 patients after surgical stabilization of long bone fractures of which six patients had impaired fracture healing were included in this study. Life-style and patient related factors with a known effect on DKK1 and SOST were recorded. DKK1 and SOST concentrations were measured using enzyme-linked immunosorbent assay (ELISA) at the fracture site and in circulation. DKK1 and SOST showed a close inverse correlation. In fracture hematoma and immediately after trauma DKK1 levels were significantly reduced while SOST levels were significantly increased, compared to healthy control. Postoperatively, DKK1 peaked at week 2 and SOST at week 8, again demonstrating a close negative correlation. Age and smoking status affected the balance of DKK1 and SOST, while type 2 diabetes and sex did not demonstrate a significant influence. Early postoperative elevation of SOST without compensatory DKK1 decrease was associated with fracture non-union in younger patients (< 50a). The close inverse correlation and very rapid dynamics of DKK1 and SOST locally as well as systemically suggest their critical involvement during human fracture healing. Importantly, as immediate compensatory feedback mechanism are apparent, we provide evidence that dual-blockade of DKK1 and SOST could be critical to allow for therapeutic efficiency of Wnt targeted therapies for fracture healing.
摘要：
Wnt信号传导与骨折愈合密切相关。现有数据主要依赖于啮齿动物模型。这里,我们探讨了患者局部和循环Dickkopf-1(DKK1)水平与骨折愈合的关系,并探讨了其与硬化蛋白(SOST)的关系.本研究包括69例长骨骨折手术稳定后的患者，其中6例患者骨折愈合受损。记录对DKK1和SOST有已知影响的生活方式和患者相关因素。使用酶联免疫吸附测定（ELISA）在骨折部位和循环中测量DKK1和SOST浓度。DKK1和SOST呈密切的负相关。在骨折血肿和创伤后立即DKK1水平显着降低，而SOST水平显着升高，与健康对照相比。术后,DKK1在第2周达到峰值，SOST在第8周达到峰值，再次显示出紧密的负相关。年龄和吸烟状况影响DKK1和SOST的平衡，而2型糖尿病和性别没有显着影响。术后早期SOST升高而未代偿性DKK1降低与年轻患者（<50a）的骨折不愈合有关。DKK1和SOST在局部和系统上的紧密负相关和非常快速的动力学表明，它们在人类骨折愈合过程中至关重要。重要的是,因为即时补偿反馈机制是显而易见的，我们提供的证据表明，DKK1和SOST的双重阻断对于Wnt靶向治疗骨折愈合的治疗效果至关重要。
