Inflammation Intensity-Dependent Expression of Osteoinductive Wnt Proteins Is Critical for Ectopic New Bone Formation in Ankylosing Spondylitis
Inflammation Intensity-Dependent Expression of Osteoinductive Wnt Proteins Is Critical for Ectopic New Bone Formation in Ankylosing Spondylitis
复制标题
骨诱导性 Wnt 蛋白的炎症强度依赖性表达对于强直性脊柱炎异位新骨形成至关重要
DOI：
10.1002/art.40468
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发表时间：
2018-07-01
影响因子：
13.3
通讯作者：
Li, Hui
中科院分区：
文献类型：
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作者：
Li, Xiang;Wang, Jianru;Li, Hui
目的：目的探讨强直性脊柱炎（ankylosing spondylitis，AS）炎症相关异位新骨形成的分子机制。建立模拟成骨部位局部炎症微环境的体外细胞培养体系，研究炎症与Wnt表达的关系、炎症诱导Wnt表达的调控机制以及Wnt信号在新骨形成中的作用。结果：AS患者血清和脊柱韧带组织中骨诱导Wnt蛋白表达水平均明显升高，而胶原诱导关节炎（CIA）和蛋白多糖诱导脊柱炎（PGIS）模型中Wnt蛋白表达水平明显升高。组成性低强度肿瘤坏死因子（TNF）刺激，而不是短期或高强度TNF刺激，诱导骨诱导Wnt蛋白的持续表达，随后通过NF-B（p65）和JNK/激活蛋白1（c-Jun）信号通路形成骨。此外，抑制Wnt/β-catenin或Wnt/蛋白激酶C（PKC）通路显着抑制新骨形成。在改良的CIA和PGIS模型中证实了Wnt蛋白表达的增加。在改良CIA模型的长期观察中，观察到脊柱的后凸和强直表型。抑制Wnt/β-catenin或Wnt/PKC信号通路显着降低了发病率和严重程度，这种phenotype.Conclusion：炎症强度依赖性表达的骨诱导Wnt蛋白是炎症和异位新骨形成在AS之间的一个关键环节。经典Wnt/β-catenin和非经典Wnt/PKC通路的激活是炎症诱导的新骨形成所必需的。
Objective: To investigate the molecular mechanism underlying inflammation-related ectopic new bone formation in ankylosing spondylitis (AS).MethodsSpinal tissues and sera were collected from patients with AS and healthy volunteers and examined for the expression of Wnt proteins. An in vitro cell culture system mimicking the local inflammatory microenvironment of bone-forming sites was established to study the relationship between inflammation and Wnt expression, the regulatory mechanism of inflammation-induced Wnt expression, and the role of Wnt signaling in new bone formation. Modified collagen-induced arthritis (CIA) and proteoglycan-induced spondylitis (PGIS) animal models were used to confirm the key findings in vivo.Results: The levels of osteoinductive Wnt proteins were increased in sera and spinal ligament tissues from patients with AS. Constitutive low-intensity tumor necrosis factor (TNF) stimulation, but not short-term or high-intensity TNF stimulation, induced persistent expression of osteoinductive Wnt proteins and subsequent bone formation through NF-B (p65) and JNK/activator protein 1 (c-Jun) signaling pathways. Furthermore, inhibition of either the Wnt/-catenin or Wnt/protein kinase C (PKC) pathway significantly suppressed new bone formation. The increased expression of Wnt proteins was confirmed in both the modified CIA and PGIS models. A kyphotic and ankylosing phenotype of the spine was seen during long-term observation in the modified CIA model. Inhibition of either the Wnt/-catenin or Wnt/PKC signaling pathway significantly reduced the incidence and severity of this phenotype.Conclusion: Inflammation intensity-dependent expression of osteoinductive Wnt proteins is a key link between inflammation and ectopic new bone formation in AS. Activation of both the canonical Wnt/-catenin and noncanonical Wnt/PKC pathways is required for inflammation-induced new bone formation.