WNT16 antagonises excessive canonical WNT activation and protects cartilage in osteoarthritis.
WNT16 antagonises excessive canonical WNT activation and protects cartilage in osteoarthritis.
复制标题
WNT16拮抗过多的典型WNT激活，并保护骨关节炎的软骨。
DOI：
10.1136/annrheumdis-2015-208577
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发表时间：
2017-01
影响因子：
27.4
通讯作者：
Dell'Accio F
中科院分区：
文献类型：
--
作者：
Nalesso G;Thomas BL;Sherwood JC;Yu J;Addimanda O;Eldridge SE;Thorup AS;Dale L;Schett G;Zwerina J;Eltawil N;Pitzalis C;Dell'Accio F
WNT信号传导的过度和不足激活都导致软骨破坏和骨关节炎。WNT16在损伤后的关节软骨和骨关节炎中上调。在此，我们研究了WNT16在骨关节炎中的功能及其下游分子机制。骨关节炎是由野生型和WNT16缺陷型小鼠的内侧半月板不稳定引起的。在体外和体内研究了原代软骨祖细胞和原代软骨细胞的分子机制和下游效应。在原代软骨细胞中研究了WNT 16下游的途径，并在非洲爪蟾中使用轴复制测定。WNT16缺陷小鼠发生更严重的骨关节炎，润滑素表达减少，软骨细胞凋亡增加。WNT16支持软骨表浅区祖细胞和润滑素表达的表型。WNT16缺陷小鼠骨关节炎的增加与经典WNT信号的过度激活有关。在体外，高剂量的WNT 16微弱地激活经典WNT信号传导，但是，在共刺激实验中，WNT 16降低了WNT 3a激活经典WNT通路的能力。在体内，WNT16挽救了WNT8诱导的爪蟾胚胎主轴复制。在骨关节炎中，WNT16维持平衡的经典WNT信号传导并防止有害的过度活化，从而支持祖细胞的稳态。
Both excessive and insufficient activation of WNT signalling results in cartilage breakdown and osteoarthritis. WNT16 is upregulated in the articular cartilage following injury and in osteoarthritis. Here, we investigate the function of WNT16 in osteoarthritis and the downstream molecular mechanisms. Osteoarthritis was induced by destabilisation of the medial meniscus in wild-type and WNT16-deficient mice. Molecular mechanisms and downstream effects were studied in vitro and in vivo in primary cartilage progenitor cells and primary chondrocytes. The pathway downstream of WNT16 was studied in primary chondrocytes and using the axis duplication assay in Xenopus. WNT16-deficient mice developed more severe osteoarthritis with reduced expression of lubricin and increased chondrocyte apoptosis. WNT16 supported the phenotype of cartilage superficial-zone progenitor cells and lubricin expression. Increased osteoarthritis in WNT16-deficient mice was associated with excessive activation of canonical WNT signalling. In vitro, high doses of WNT16 weakly activated canonical WNT signalling, but, in co-stimulation experiments, WNT16 reduced the capacity of WNT3a to activate the canonical WNT pathway. In vivo, WNT16 rescued the WNT8-induced primary axis duplication in Xenopus embryos. In osteoarthritis, WNT16 maintains a balanced canonical WNT signalling and prevents detrimental excessive activation, thereby supporting the homeostasis of progenitor cells.