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首页> 外文期刊>Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research >EphA4 receptor is a novel negative regulator of osteoclast activity
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EphA4 receptor is a novel negative regulator of osteoclast activity

机译：EphA4受体是破骨细胞活性的新型负调节剂

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Of the ephrin (Eph) receptors, mature osteoclasts express predominantly EphA4. This study sought to determine if EphA4 has a regulatory role in osteoclasts. Treatment of RAW/C4 cells with Epha4 small interfering RNAs (siRNAs) increased average size, Ctsk mRNA expression level, and bone resorption activity of the derived osteoclast-like cells. Activation of the EphA4 signaling in osteoclast precursors with EfnA4-fc chimeric protein reduced cell size and resorption activity of the derived osteoclasts. Homozygous Epha4 null mice had substantially less trabecular bone in femur and vertebra compared to wild-type controls. The bone loss was due to a decrease in trabecular number and an increase in trabecular spacing, but not to an increase in osteoclast-lined bone surface or an increase in the number of osteoclasts on bone surface. Dynamic histomorphometry and serum biomarker analyses indicate that bone formation in Epha4 null mice was reduced slightly but not significantly. Osteoclasts of Epha4 null mice were also larger, expressed higher levels of Mmp3 and Mmp9 mRNAs, and exhibited greater bone resorption activity than wild-type osteoclasts in vitro. Deficient Epha4 expression had no effects on the total number of osteoclast formed in response to receptor activator of NF-κB ligand nor on apoptosis of osteoclasts in vitro. It also did not affect the protein-tyrosine phosphorylation status of its ligands, EfnB2, EfnA2, and EfnA4, in osteoclasts. Deficient Epha4 expression in Epha4 null osteoclasts activated the β3-integrin signaling through reduced phosphorylation of the tyr-747 residue, which led to increased binding of the stimulatory talin and reduced binding of the inhibitory Dok1 to β3-integrin. This in turn activated Vav3 and the bone resorption activity of osteoclasts. In conclusion, we demonstrate for the first time that EphA4 is a potent negative regulator of osteoclastic activity, mediated in part through increased Dok1 binding to β3-integrin via an increase in EphA4-dependent tyr-747 phosphorylation.
机译：在ephrin（Eph）受体中，成熟的破骨细胞主要表达EphA4。这项研究试图确定EphA4在破骨细胞中是否具有调节作用。用Epha4小干扰RNA（siRNA）处理RAW / C4细胞会增加衍生的破骨细胞样细胞的平均大小，Ctsk mRNA表达水平和骨吸收活性。用EfnA4-fc嵌合蛋白激活破骨细胞前体中的EphA4信号减少了细胞大小和衍生的破骨细胞的吸收活性。与野生型对照相比，纯合Epha4缺失小鼠的股骨和椎骨小梁骨少得多。骨损失是由于骨小梁数目减少和骨小梁间距增加，而不是由于破骨细胞衬里的骨表面增加或骨表面破骨细胞数目增加。动态组织形态测定法和血清生物标记分析表明，Epha4缺失小鼠的骨形成略有减少，但没有明显减少。与野生型破骨细胞相比，Epha4缺失小鼠的破骨细胞也更大，表达的Mmp3和Mmp9 mRNA含量更高，并且具有更高的骨吸收活性。缺乏Epha4表达对响应NF-κB配体受体激活物的破骨细胞总数没有影响，也对体外破骨细胞凋亡没有影响。它也不会影响破骨细胞中其配体EfnB2，EfnA2和EfnA4的蛋白质酪氨酸磷酸化状态。 Epha4空破骨细胞中Epha4表达不足，通过减少tyr-747残基的磷酸化来激活β3-整联蛋白信号传导，这导致刺激性塔林的结合增加，抑制性Dok1与β3-整联蛋白的结合减少。这又激活了Vav3和破骨细胞的骨吸收活性。总之，我们首次证明EphA4是破骨细胞活性的有效负调节剂，部分通过通过增加EphA4依赖的tyr-747磷酸化而增加的Dok1与β3-整联蛋白的结合介导。

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