Deletion of the receptor tyrosine kinase Tyro3 inhibits synovial hyperplasia and bone damage in arthritis
Deletion of the receptor tyrosine kinase Tyro3 inhibits synovial hyperplasia and bone damage in arthritis
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DOI：
10.1136/annrheumdis-2012-202907
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发表时间：
2014-04-01
影响因子：
27.4
通讯作者：
Schett, Georg
中科院分区：
文献类型：
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作者：
Ruiz-Heiland, Gisela;Zhao, Yi;Schett, Georg
目的探讨酪氨酸激酶Tyro 3与关节炎的关系。Tyro 3是生长停滞特异性蛋白6（GAS 6）的配体，是参与细胞存活的受体酪氨酸激酶。Tyro 3和GAS 6在关节炎滑膜中表达，体外研究表明它们在破骨细胞differentiation.MethodsBone中的作用通过显微CT和Tyro 3缺陷（Tyro 3 −/−）和野生型小鼠的组织形态计量学进行评估。在两种基因型中诱导关节炎，并通过ELISA测量Gas 6水平。滑膜炎，滑膜增生，骨质侵蚀，破骨细胞活化和破骨细胞基因表达分别进行了评估，通过组织形态计量学和逆转录酶-PCR。在Tyro 3 −/−和野生型小鼠中进行体外破骨细胞分化试验。此外，在人细胞中评估了Tyro 3和GAS 6对人滑膜成纤维细胞增殖和破骨细胞生成的影响。ResultsTyro 3 −/−小鼠的骨量显著高于野生型同窝小鼠。关节炎的诱导增加GAS 6血清水平。与对照组相比，关节炎Tyro 3 −/−小鼠的滑膜增生、破骨细胞数量和骨损伤较少。在Tyro 3 −/−小鼠中，破骨细胞相关受体和核因子-κB受体激活剂的体内表达以及体外破骨细胞生成受损。GAS 6还诱导滑膜成纤维细胞增殖和破骨细胞分化在人类细胞中的Tyro 3-dependent marty.ConclusionsThese研究结果表明，Tyro 3是一个关键的信号滑膜增生，破骨细胞分化和骨侵蚀关节炎。因此，GAS 6和Tyro 3构成了抑制滑膜增生和相关骨侵蚀的治疗靶标。
ObjectiveTo test whether the tyrosine kinase Tyro3 affects arthritis. Tyro3, the ligand of growth arrest–specific protein 6 (GAS6) is a receptor tyrosine kinase involved in cell survival. Tyro3 and GAS6 are expressed in the arthritic synovium, and in vitro studies have shown their role in osteoclast differentiation.MethodsBone was assessed by micro CT and histomorphometry in Tyro3-deficient (Tyro3−/−) and wild-type mice. Arthritis was induced in both genotypes, and Gas6 level was measured by ELISA. Synovitis, synovial hyperplasia, bone erosion, osteoclast activation and osteoclast gene expression were assessed by histomorphometry and reverse transcriptase–PCR, respectively. In vitro osteoclast differentiation assays were performed in Tyro3−/−and wild-type mice. Furthermore, effects of Tyro3 and GAS6 on human synovial fibroblast proliferation and osteoclastogenesis were assessed in human cells.ResultsTyro3−/−mice had significantly higher bone mass than wild-type littermates. Induction of arthritis increased GAS6 serum levels. Arthritic Tyro3−/−mice showed less synovial hyperplasia, osteoclast numbers and bone damage compared with controls. In vivo expression of osteoclast-associated receptor and receptor activator of nuclear factor-κB and in vitro osteoclastogenesis were impaired in Tyro3−/−mice. GAS6 also induced synovial fibroblast proliferation and osteoclast differentiation in human cells in Tyro3-dependent manner.ConclusionsThese findings indicate that Tyro3 is a critical signal for synovial hyperplasia, osteoclast differentiation and bone erosion during arthritis. GAS6 and Tyro3 therefore constitute therapeutic targets to inhibit synovial hyperplasia and associated bone erosion.