Department of Experimental Medicine I, Nikolaus-Fiebiger-Zentrum für Molekulare Medizin, University of Erlangen-Nuremberg, Erlangen, Germany.
J Cell Physiol. 2012 May;227(5):2207-16. doi: 10.1002/jcp.22957.
Wnt inhibitory factor 1 (Wif-1) is a secreted antagonist of Wnt signalling. We recently demonstrated that this molecule is expressed predominantly in superficial layers of epiphyseal cartilage but also in bone and tendon. Moreover, we showed that Wif-1 is capable of binding to several cartilage-related Wnt ligands and interferes with Wnt3a-dependent Wnt signalling in chondrogenic cells. Here we provide evidence that the biological function of Wif-1 may not be confined to the modulation of Wnt signalling but appears to include the regulation of other signalling pathways. Thus, we show that Wif-1 physically binds to connective tissue growth factor (CTGF/CCN2) in vitro, predominantly by interaction with the C-terminal cysteine knot domain of CTGF. In vivo such an interaction appears also likely since the expression patterns of these two secreted proteins overlap in peripheral zones of epiphyseal cartilage. In chondrocytes CTGF has been shown to induce the expression of cartilage matrix genes such as aggrecan (Acan) and collagen2a1 (Col2a1). In this study we demonstrate that Wif-1 is capable to interfere with CTGF-dependent induction of Acan and Col2a1 gene expression in primary murine chondrocytes. Conversely, CTGF does not interfere with Wif-1-dependent inhibition of Wnt signalling. These results indicate that Wif-1 may be a multifunctional modulator of signalling pathways in the cartilage compartment.
Wnt 抑制因子 1（Wif-1）是 Wnt 信号的一种分泌性拮抗剂。我们最近证明，这种分子主要在骺软骨的浅层表达，但也在骨和肌腱中表达。此外，我们表明 Wif-1 能够与几种与软骨相关的 Wnt 配体结合，并干扰软骨细胞中 Wnt3a 依赖性 Wnt 信号。在这里，我们提供的证据表明，Wif-1 的生物学功能可能不仅限于调节 Wnt 信号，而且似乎还包括调节其他信号通路。因此，我们表明 Wif-1 在体外与结缔组织生长因子（CTGF/CCN2）物理结合，主要通过与 CTGF 的 C 末端半胱氨酸结结构域相互作用。在体内，这种相互作用似乎也很可能，因为这两种分泌蛋白的表达模式在骺软骨的外周区重叠。在软骨细胞中，CTGF 已被证明能诱导软骨基质基因如聚集蛋白聚糖（Acan）和 Col2a1 的表达。在这项研究中，我们证明 Wif-1 能够干扰 CTGF 依赖性诱导的原代鼠软骨细胞中 Acan 和 Col2a1 基因表达。相反，CTGF 不干扰 Wif-1 依赖性抑制 Wnt 信号。这些结果表明，Wif-1 可能是软骨细胞中信号通路的多功能调节剂。
