Smad3 deficiency leads to mandibular condyle degradation via the sphingosine 1-phosphate (S1P)/S1P3 signaling axis.
Smad3 deficiency leads to mandibular condyle degradation via the sphingosine 1-phosphate (S1P)/S1P3 signaling axis.
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DOI：
10.1016/j.ajpath.2015.06.015
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发表时间：
2015-10
期刊：
影响因子：
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通讯作者：
Hiroki Mori;T. Izawa;E. Tanaka
中科院分区：
文献类型：
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作者：
Hiroki Mori;T. Izawa;E. Tanaka
颞下颌关节骨关节炎是一种退行性疾病，其特征是软骨永久性破坏。转化生长因子 (TGF)-β 是骨基质中最丰富的细胞因子之一，可调节骨祖细胞的迁移。据推测，TGF-β/Smad3 信号传导通过影响 1-磷酸鞘氨醇 (S1P)/S1P 受体信号传导和软骨细胞迁移来影响软骨稳态。因此，我们研究了 TGF-β/Smad3 和 S1P/S1P 受体信号之间可能发生串扰以维持髁软骨并预防颞下颌关节骨关节炎的分子机制。通过微型计算机断层扫描在 Smad3−/− 小鼠中观察到髁软骨下骨的异常，包括骨矿物质密度和微观结构的动态变化。无细胞区域和蛋白多糖损失表征了存在的软骨退化，并且还检测到凋亡软骨细胞和基质金属蛋白酶13+软骨细胞数量的增加。此外，Smad3−/−小鼠髁突软骨中S1P受体3（S1P3）的表达显着下调，而S1P1或S1P2则不然。通过使用RNA干扰技术和药理学工具，发现S1P以S1P3/TGF-β II型受体依赖性方式反式激活Smad3，并且发现S1P3是TGF-β诱导的软骨细胞迁移以及通过Rac1、RhoA和Cdc42进行下游信号转导所必需的。综上所述，这些结果表明Smad3/S1P3信号通路在颞下颌关节骨关节炎的发病机制中发挥着重要作用。
Temporomandibular joint osteoarthritis is a degenerative disease that is characterized by permanent cartilage destruction. Transforming growth factor (TGF)-β is one of the most abundant cytokines in the bone matrix and is shown to regulate the migration of osteoprogenitor cells. It is hypothesized that TGF-β/Smad3 signaling affects cartilage homeostasis by influencing sphingosine 1-phosphate (S1P)/S1P receptor signaling and chondrocyte migration. We therefore investigated the molecular mechanisms by which crosstalk may occur between TGF-β/Smad3 and S1P/S1P receptor signaling to maintain condylar cartilage and to prevent temporomandibular joint osteoarthritis. Abnormalities in the condylar subchondral bone, including dynamic changes in bone mineral density and microstructure, were observed inSmad3−/−mice by microcomputed tomography. Cell-free regions and proteoglycan loss characterized the cartilage degradation present, and increased numbers of apoptotic chondrocytes and matrix metalloproteinase 13+chondrocytes were also detected. Furthermore, expression of S1P receptor 3 (S1P3), but not S1P1or S1P2, was significantly down-regulated in the condylar cartilage ofSmad3−/−mice. By using RNA interference technology and pharmacologic tools, S1P was found to transactivate Smad3 in an S1P3/TGF-β type II receptor-dependent manner, and S1P3was found to be required for TGF-β–induced migration of chondrocyte cells and downstream signal transduction via Rac1, RhoA, and Cdc42. Taken together, these results indicate that the Smad3/S1P3signaling pathway plays an important role in the pathogenesis of temporomandibular joint osteoarthritis.