Cytokine-like 1 Knock-out Mice (Cytl1-/-) Show Normal Cartilage and Bone Development but Exhibit Augmented Osteoarthritic Cartilage Destruction
Cytokine-like 1 Knock-out Mice (Cytl1-/-) Show Normal Cartilage and Bone Development but Exhibit Augmented Osteoarthritic Cartilage Destruction
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DOI：
10.1074/jbc.m111.218065
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发表时间：
2011-08-05
影响因子：
4.8
通讯作者：
Chun, Jang-Soo
中科院分区：
文献类型：
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作者：
Jeon, Jimin;Oh, Hwanhee;Chun, Jang-Soo
我们已经表明，细胞因子样1（Cytl1）是一种新型的自分泌调节因子，可调节小鼠间充质细胞的软骨形成（Kim, J. S., Ryoo, Z. Y., 和Chun, J. S.（2007年）《生物化学杂志》282卷，29359 - 29367页）。在之前的这项工作中，我们发现间充质细胞中Cytl1的表达非常低，在软骨形成过程中显著增加，而在肥大成熟过程中（无论是在体内还是体外）则降低。此外，外源性添加Cytl1或其异位表达会导致小鼠肢芽间充质细胞的软骨分化。在当前的研究中，我们构建了Cytl1基因敲除（Cytl1⁻/⁻）小鼠以研究Cytl1在体内的作用。Cytl1基因的缺失并不影响软骨形成或软骨发育。Cytl1⁻/⁻小鼠也显示出正常的软骨内骨化和长骨发育。此外，关节软骨的超微结构特征，如基质组织和软骨细胞形态，在野生型和Cytl1⁻/⁻小鼠中是相似的。然而，Cytl1⁻/⁻小鼠对骨关节炎（OA）软骨破坏更为敏感。与野生型同窝小鼠相比，在小鼠膝关节内侧半月板失稳时，Cytl1⁻/⁻小鼠表现出更严重的OA软骨破坏。此外，在人类和实验小鼠的OA软骨中，Cytl1的表达水平显著降低。综上所述，我们的研究结果表明，Cytl1并非调节软骨和骨发育，而是软骨内稳态维持所必需的，并且Cytl1功能的缺失与小鼠实验性OA软骨破坏有关。
We have shown that cytokine-like 1 (Cytl1) is a novel autocrine regulatory factor that regulates chondrogenesis of mouse mesenchymal cells (Kim, J. S., Ryoo, Z. Y., and Chun, J. S. (2007) J. Biol. Chem. 282, 29359-29367). In this previous work, we found that Cytl1 expression was very low in mesenchymal cells, increased dramatically during chondrogenesis, and decreased during hypertrophic maturation, both in vivo and in vitro. Moreover, exogenous addition or ectopic expression of Cytl1 caused chondrogenic differentiation of mouse limb bud mesenchymal cells. In the current study, we generated a Cytl1 knockout (Cytl1(-/-)) mouse to investigate the in vivo role of Cytl1. Deletion of the Cytl1 gene did not affect chondrogenesis or cartilage development. Cytl1(-/-) mice also showed normal endochondral ossification and long bone development. Additionally, ultrastructural features of articular cartilage, such as matrix organization and chondrocyte morphology, were similar in wild-type and Cytl1(-/-) mice. However, Cytl1(-/-) mice were more sensitive to osteoarthritic (OA) cartilage destruction. Compared with wild-type littermates, Cytl1(-/-) mice showed more severe OA cartilage destruction upon destabilization of the medial meniscus of mouse knee joints. In addition, expression levels of Cytl1 were markedly decreased in OA cartilage of humans and experimental mice. Taken together, our results suggest that, rather than regulating cartilage and bone development, Cytl1 is required for the maintenance of cartilage homeostasis, and loss of Cytl1 function is associated with experimental OA cartilage destruction in mice.