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Rac1 Inhibition Via Srgap2 Restrains Inflammatory Osteoclastogenesis and Limits the Clastokine, SLIT3.
Journal of Bone and Mineral Research ( IF 6.2 ) Pub Date : 2020-01-09 , DOI: 10.1002/jbmr.3945
Bongjin Shin 1 , Justine Kupferman 2 , Ewoud Schmidt 2 , Franck Polleux 2 , Anne M Delany 3 , Sun-Kyeong Lee 1
Affiliation  

The Rac1-specific guanosine triphosphatase (GTPase)-activating protein Slit-Robo GAP2 (Srgap2) is dramatically upregulated during RANKL-induced osteoclastogenesis. Srgap2 interacts with the cell membrane to locally inhibit activity of Rac1. In this study, we determined the role of Srgap2 in the myeloid lineage on bone homeostasis and the osteoclastic response to TNFα treatment. The bone phenotype of mice specifically lacking Srgap2 in the myeloid lineage (Srgap2 f/f :LysM-Cre; Srgap2 conditional knockout [cKO]) was investigated using histomorphometric analysis, in vitro cultures and Western blot analysis. Similar methods were used to determine the impact of TNFα challenge on osteoclast formation in Srgap2 cKO mice. Bone parameters in male Srgap2 cKO mice were unaffected. However, female cKO mice displayed higher trabecular bone volume due to increased osteoblast surface and bone formation rate, whereas osteoclastic parameters were unaltered. In vitro, cells from Srgap2 cKO had strongly enhanced Rac1 activation, but RANKL-induced osteoclast formation was unaffected. In contrast, conditioned medium from Srgap2 cKO osteoclasts promoted osteoblast differentiation and had increased levels of the bone anabolic clastokine SLIT3, providing a possible mechanism for increased bone formation in vivo. Rac1 is rapidly activated by the inflammatory cytokine TNFα. Supracalvarial injection of TNFα caused an augmented osteoclastic response in Srgap2 cKO mice. In vitro, cells from Srgap2 cKO mice displayed increased osteoclast formation in response to TNFα. We conclude that Srgap2 plays a prominent role in limiting osteoclastogenesis during inflammation through Rac1, and restricts expression of the paracrine clastokine SLIT3, a positive regulator of bone formation. © 2019 American Society for Bone and Mineral Research.

中文翻译:

通过 Srgap2 抑制 Rac1 抑制炎症性破骨细胞生成并限制 Clastokine,SLIT3。

Rac1 特异性鸟苷三磷酸酶 (GTPase) 激活蛋白 Slit-Robo GAP2 (Srgap2) 在 RANKL 诱导的破骨细胞生成过程中显着上调。Srgap2 与细胞膜相互作用以局部抑制 Rac1 的活性。在这项研究中,我们确定了 Srgap2 在骨髓谱系中对骨稳态和破骨细胞对 TNFα 治疗的反应的作用。使用组织形态学分析、体外培养和蛋白质印迹分析研究了骨髓谱系中特别缺乏 Srgap2 的小鼠的骨表型 (Srgap2 f/f:LysM-Cre; Srgap2 条件性敲除 [cKO])。类似的方法用于确定 TNFα 攻击对 Srgap2 cKO 小鼠中破骨细胞形成的影响。雄性 Srgap2 cKO 小鼠的骨骼参数不受影响。然而,由于成骨细胞表面和骨形成率增加,雌性 c​​KO 小鼠表现出更高的骨小梁体积,而破骨细胞参数没有改变。在体外,来自 Srgap2 cKO 的细胞强烈增强了 Rac1 的激活,但 RANKL 诱导的破骨细胞形成不受影响。相比之下,来自 Srgap2 cKO 破骨细胞的条件培养基促进成骨细胞分化并增加了骨合成代谢 clastokine SLIT3 的水平,为体内骨形成增加提供了可能的机制。Rac1 被炎性细胞因子 TNFα 迅速激活。颅骨上注射 TNFα 导致 Srgap2 cKO 小鼠的破骨细胞反应增强。在体外,来自 Srgap2 cKO 小鼠的细胞显示出对 TNFα 反应的破骨细胞形成增加。我们得出结论,Srgap2 通过 Rac1 在炎症期间在限制破骨细胞生成中起重要作用,并限制旁分泌 clastokine SLIT3(骨形成的正调节剂)的表达。© 2019 美国骨与矿物研究学会。
更新日期:2020-01-09
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